Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors

ABSTRACT

The present application describes sulfonylaminovalerolactams and derivatives thereof of Formula I:  
                 
or pharmaceutically acceptable salt forms thereof, wherein ring G is a mono- or bicyclic carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 10/429,461filed on May 5, 2003, which claims the priority benefits of U.S.Provisional application Ser. No. 60/378,313, filed May 6, 2002, thedisclosures of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates generally to sulfonylaminovalerolactams andderivatives thereof which are inhibitors of trypsin-like serine proteaseenzymes, especially factor Xa, pharmaceutical compositions containingthe same, and methods of using the same as anticoagulant agents fortreatment of thromboembolic disorders.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,032,602 shows 2-pyridones of the following formula.

These compounds are inhibitors of HMG-CoA reductase. These compounds arenot described as being useful for inhibiting factor Xa and are notconsidered to be part of the present invention.

WO97/36900 describes inhibitors of farnesyl-protein transferase of theformula.

WO97/36900 does not-consider inhibition of factor Xa however. Thecompounds of WO97/36900 are not considered to be part of the presentinvention.

WO99/31506 and WO99/31507 describe solution phase syntheses of lactamsof the formula.

The lactams described in WO99/31506 and WO99/31507 are not considered tobe part of the present invention.

WO095/14012 illustrates protease inhibitors of the formula.

This formula represents pyrones when Y is unsubstituted or substitutednitrogen. However, the compounds of WO95/14012 are not considered to bepart of the present invention.

EP 0,908,764 depicts photographic developers of the formula below.

Careful selection of variables can lead one to pyrones. But, thecompounds of EP 0,908,764 are not considered to be part of the presentinvention.

EP 0,454,444 describes glutarimide derivatives of the following formula.

can be O, R¹ can be an alkyl, alkoxy, or halo-substituted benzyl, and R₉can be a cyclic moiety. These compounds are indicated to be herbicides.The compounds of EP 0,454,444 are not considered to be part of thepresent invention.

WO99/42455 illustrates antiviral agents of the formula.

R¹ can potentially be a cyclic amide substituted by an aryl amine. Thering containing X and Y is a 5 or 6-membered heteroaromatic ring. Thecompounds shown in WO99/42455 are not considered to be part of thepresent invention.

U.S. Pat. No. 5,998,447 shows heterocycles of the following formula.

B can be phenylene; W can be substituted phenylalkylene; c, d, e, f, g,and h can all be 0; and, E can be tetrazole. These compounds areinhibitors of leucocyte adhesion and/or antagonists of VLA-4. Tetrazolesubstituted compounds of this sort are not considered to be part of thepresent invention.

EP 0,522,606 depicts pyridine derivatives of the following formula.

R can be substituted pyridine, X can be O, A is a carbon atom that canbe part of a ring (i.e., a 1,1-substituted ring), Y can be O, and R₃ andR₄ can combine for form a cyclic lactam containing an substitutedaralkyl. Compounds of this sort are not considered to be part of thepresent invention.

WO/0069826, WO/0069832, WO/0069833, and WO/0069834 relate to coagulationcascade inhibitors that are 1,3-disubsituted pyridones of the formulashown below, or aza-substituted derivatives.

B and Y⁰ are preferably cyclic moieties. A, Ψ, K, and E⁰ are preferablylinkers. Pyridones and aza-pyridones of this sort are not considered tobe part of the present invention.

Activated factor Xa, whose major practical role is the generation ofthrombin by the limited proteolysis of prothrombin, holds a centralposition that links the intrinsic and extrinsic activation mechanisms inthe final common pathway of blood coagulation. The generation ofthrombin, the final serine protease in the pathway to generate a fibrinclot, from its precursor is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it iscalculated that one molecule of factor Xa can generate 138 molecules ofthrombin (Elodi, S., Varadi, K.: Optimization of conditions for thecatalytic effect of the factor IXa-factor VIII Complex: Probable role ofthe complex in the amplification of blood coagulation. Thromb. Res.1979, 15, 617-629), inhibition of factor Xa may be more efficient thaninactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are neededas potentially valuable therapeutic agents for the treatment ofthromboembolic disorders. It is thus desirable to discover new factor Xainhibitors. In addition, it is also desirable to find new compounds withimproved pharmacological characteristics compared with known factor Xainhibitors. For example, it is preferred to find new compounds withimproved factor Xa inhibitory activity and selectivity for factor Xaversus other serine proteases (i.e., trypsin). It is also desirable andpreferable to find compounds with advantageous and improvedcharacteristics in one or more of the following categories, but are notlimited to: (a) pharmaceutical properties; (b) dosage requirements; (c)factors which decrease blood concentration peak-to-troughcharacteristics; (d) factors that increase the concentration of activedrug at the receptor; (e) factors that decrease the liability forclinical drug-drug interactions; (f) factors that decrease the potentialfor adverse side-effects; and, (g) factors that improve manufacturingcosts or feasibility.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novelsulfonylaminovalerolactams and derivatives thereof that are useful asfactor Xa inhibitors or pharmaceutically acceptable salts or prodrugsthereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides novel compounds for use in therapy.

The present invention provides the use of novel compounds for themanufacture of a medicament for the treatment of a thromboembolicdisorder.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors'discovery thatsulfonylaminovalerolactams of Formula I:

wherein G, G¹, A and B are defined below, or pharmaceutically acceptablesalt or prodrug forms thereof, are effective factor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in an embodiment, the present invention provides a novel compoundof formula Ia, Ib, or Ic:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;the central lactam ring is substituted with 0-2 R^(1a);

-   G is a group of formula IIa or IIb:-   ring D, including the two atoms of ring E to which it is attached,    is a 5-6 membered ring consisting of: carbon atoms and 0-2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p);-   ring D is substituted with 0-2 R and there are 0-3 ring double    bonds;-   E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and    pyridazinyl, and is substituted with 1-3 R;-   alternatively, ring D is absent, and ring E is selected from phenyl,    pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,    imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl,    and ring E is substituted with 1-3 R;-   alternatively, ring D is absent, ring E is selected from phenyl,    phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl,    pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and    thiazolyl, and ring E is substituted with 1 R and with a 5-6    membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), wherein    the 5-6 membered heterocycle is substituted with 0-2 carbonyls and    1-2 R and has 0-3 ring double bonds;-   R is selected from H, C₁₋₄ alkyl, F, Cl, Br, I, OH, OCH₃, OCH₂CH₃,    OCH(CH₃)₂, OCH₂CH₂CH₃, CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹,    NR⁸CH(═NR⁷), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, C(═NH)NH₂, CH₂NH₂,    CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃ alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃    alkyl), CH₂CH₂N(C₁₋₃ alkyl)₂, (CR⁸R⁹)_(t)C(O)H,    (CR⁸R⁹)_(t)C(O)R^(2c), (CR⁸R⁹)_(t)NR⁷R⁸, (CR⁸R⁹)_(t)C(O)NR⁷R⁸,    (CR⁸R⁹)_(t)NR⁷C(O)R⁷, (CR⁸R⁹)_(t)OR³, (CR⁸R⁹)_(t)S(O)_(p)NR⁷R⁸,    (CR⁸R⁹)_(t)NR⁷S(O)_(p)R⁷, (CR⁸R⁹)_(t)SR³, (CR⁸R⁹)_(t)S(O)R³,    (CR⁸R⁹)_(t)S(O)₂R³, and OCF₃;-   alternatively, when 2 R groups are attached to adjacent atoms, they    combine to form methylenedioxy or ethylenedioxy;-   G₁ is selected from H, (CR³R^(3a))₁₋₂C(O)R²,    (CR³R^(3a))₁₋₂NR²R^(2a), (CR³R^(3a))₁₋₂OR²,    (CR³R^(3a))₁₋₂S(O)_(p)R², (CR³R^(3a))₁₋₂NR²C(O)R²,    (CR³R^(3a))₁₋₂NR²C(O)NR²R^(2a), (CR³R^(3a))₁₋₂NR²C(O)OR²,    (CR³R^(3a))₁₋₂S(O)₂NR²R^(2a), (CR³R^(3a))₁₋₂NR²S(O)₂NR²R^(2a),    (CR³R^(3a))₁₋₂OC(O)R², (CR³R^(3a))₁₋₂C(O)OR²,    (CR³R^(3a))₁₋₂C(O)NR²R^(2a),    (CR³R^(3a))₁₋₂C(O)NR²(CR³R^(3a))(CR³R^(3a))₁₋₂OR²,    (CR³R^(3a))₁₋₂C(O)NR²(CR³R^(3a))(CR³R^(3a))₁₋₂NR²R^(2a),    (CR³R^(3a))C(O)NR²(CR³R^(3a))₁₋₂C(O)NR²R^(2a),    (CR³R^(3a))C(O)NR²(CR³R^(3a))₁₋₂C(O)OR², C₁₋₆ alkyl substituted with    0-2 R^(1a), C₂₋₆ alkenyl substituted with 0-2 R^(1a), C₂₋₆ alkynyl    substituted with 0-2 R^(1a), (CR³R^(3a))₀₋₄—C₃₋₁₀ carbocycle    substituted with 0-3 R^(1a), and (CR³R^(3a))₀₋₄-5-12 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-3 R^(1a);-   A is selected from:    -   C₃₋₁₀ carbocycle substituted with 0-2 R⁴, and    -   5-12 membered heterocycle consisting of: carbon atoms and 1-4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0-2 R⁴;-   B is selected from X—Y—R^(4a), N(B¹)C(O)C(R³R^(3g))₁₋₄NB²B³, and    provided that the central lactam ring and B are attached to    different atoms on A and that the A-X—N moiety forms other than a    N—N—N group;-   B¹ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —(CH₂)₀₋₂—C₃₋₇    carbocycle substituted with 0-2 R^(4b), and —(CH₂)₀₋₂-5-6 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-2 R^(4b);-   B² is selected from H, C₁₋₆ alkyl substituted with 0-2 R^(4c),    C(O)R^(2e), C(O)OR^(2d), C(O)NR^(2d)R^(2d),    C(O)NH(CH₂)₂NR^(2d)R^(2d), SO₂NR^(2d)R^(2d), C(O)NHSO₂—C₁₋₄ alkyl,    and S(O)_(p)R^(5a);-   B³ is selected from H, C₁₋₆ alkyl substituted with 0-2 R^(4c),    —(CH₂)₀₋₂-3-6 membered carbocycle substituted with 0-2 R⁵, and a    —(CH₂)₀₋₂-4-6 membered heterocycle consisting of: carbon atoms and    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-2 R⁵;-   alternatively, NB²B³ is a 3-8 membered heterocycle consisting of:    the shown N, carbon atoms, and 0-3 additional heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-2 R⁵;-   ring Q is a 4-7 membered lactam consisting of, in addition to the    amide group shown, carbon atoms and 0-2 heteroatoms selected from    NR^(4c), O, S, S(O), and S(O)₂, wherein:    -   0-2 double bonds are present within the ring and the ring is        substituted with 0-2 R^(4a);-   alternatively, ring Q is a 4-7 membered lactam to which another ring    is fused, wherein:    -   the lactam consists of, in addition to the shown amide group,        carbon atoms and 0-2 heteroatoms selected from NR^(4c), O, S,        S(O), and S(O)₂ and 0-2 double bonds are present within the        ring;    -   the fusion ring is phenyl or a 5-6 membered heteroaromatic        consisting of carbon atoms and 0-2 NR^(4c), O, S, S(O), and        S(O)₂;    -   ring Q, which includes the lactam ring and the fusion ring, is        substituted with 0-3 R^(4a);-   X is absent or is selected from —(CR²R^(2a))₁₋₄—,    —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR^(1b))—, —CR²(NR^(1b)R²)—,    —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)—,    —S(O)₂—, —SCR²R^(2a)—, —S(O)CR²R^(2a)—, —S(O)₂CR²R^(2a)—,    CR²R^(2a)S—, —CR²R^(2a)S(O)—, —CR²R^(2a)S(O)₂—, —S(O)₂NR²—,    —S(O)₂NR²CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂—,    —CR²R^(2a)NR²S(O)₂—, —NR²S(O)₂CR²R^(2a)—, —NR²C(O)—, —C(O)NR²—,    —NR²C(O)CR²R^(2a)—, —C(O)NR²CR²R^(2a)—, —CR²R^(2a)NR²C(O)—,    —CR²R^(2a)C(O)NR²—, NR², —NR²CR²R^(2a)—, CR²R^(2a)NR²—, O,    —OCR²R^(2a)—, and —CR²R^(2a)O—;-   Y is selected from CY¹Y²R^(4a), a C₃₋₁₀ carbocycle, and 3-10    membered heterocycle, wherein the carobocycle or heterocycle    consists of carbon atoms and 0-4 heteroatoms selected from N, O, and    S(O)_(p), the carbocycle or heterocycle further comprises 0-4 double    bonds and 0-2 carbonyl groups, and the carbocycle or heterocycle is    substituted with 0-2 R⁴;-   Y¹and Y² are independently C₁₋₄ alkyl substituted with 0-2 R⁴;-   R^(1a), at each occurrence, is selected from H,    —(CR³R^(3a))_(r)—R^(1b), —(CR³R^(3a))_(r)—CR³R^(1b)R^(1b),    —(CR³R^(3a))_(r)—O—(CR³R^(3a))_(r)—R^(1b), —C₂₋₆ alkenylene-R^(1b),    —C₂₋₆ alkynylene-R^(1b), —(CR³R^(3a))^(r)—C(═NR^(1b))NR³R^(1b),    NR³(CR³R^(3a))_(t)R^(1c), O(CR³R^(3a))_(t)R^(1c),    (CR³R^(3a))_(r)SCR³R^(3a)R^(1c),    (CR³R^(3a))_(r)NR³(CR³R^(3a))_(r)R^(1b),    (CR³R^(3a))_(r)C(O)NR²(CR³R^(3a))_(r)R^(1b),    CO₂(CR³R^(3a))_(t)R^(1b), O(CR³R^(3a))_(t)R^(1b),    (CR³R^(3a))_(r)S(CR³R^(3a))_(r)R^(1b),    S(O)_(p)(CR³R^(3a))_(r)R^(1d), O(CR³R^(3a))_(r)R^(1d),    NR³(CR³R^(3a))_(r)R^(1d), OC(O)NR³(CR³R^(3a))_(r)R^(1d),    NR³C(O)NR³(CR³R^(3a))_(r)R^(1d), NR³C(O)O(CR³R^(3a))_(r)R^(1d), and    NR³C(O)(CR³R^(3a))_(r)R^(1d), provided that R^(1a) forms other than    an N-halo, N—S, O—O , or N—CN bond;-   alternatively, when two R^(1a) groups are attached to the same    carbon atom, together with the carbon atom to which they are    attached they form a 3-10 membered carbocyclic or heterocyclic ring    consisting of: carbon atoms and 0-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p), this ring being substituted    with 0-2 R⁴ and 0-3 ring double bonds;-   R^(1b) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —NO₂,    —CHO, (CF₂)_(r)CF₃, (CR³R^(3a))_(r)OR², NR²R^(2a), C(O)R^(2b),    CO₂R^(2b), OC(O)R², (CF₂)_(r)CO₂R^(2a), S(O)_(p)R^(2b),    NR²(CH₂)_(r)OR², C(═NR^(2c))NR²R^(2a), NR²(O)R^(2b), NR²C(O)NR²R 2a,    NR²C(O)₂R^(2a), OC(O)NR²R^(2a), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR²,    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂R², C(O)NR²SO₂R², SO₂R²C(O)NR²,    SO₂NR²C(O)R², C₃₋₁₀ carbocycle substituted with 0-2 R⁴, and 4-10    membered heterocycle consisting of carbon atoms and from 1-4    heteroatoms selected from the group consisting of N, O, and S(O)_(p)    and substituted with 0-2 R⁴, provided that R^(1b) forms other than    an O—O, N-halo, N—S, or N—CN bond;-   R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),    S(O)R², S(O)₂R², and SO₂NR²R^(2a);-   R^(1d) is selected from C₃₋₆ carbocycle substituted with 0-2 R^(4b)    and 5-10 membered heterocycle consisting of carbon atoms and from    1-4 heteroatoms selected from the group consisting of N, O , and    S(O)_(p) and substituted with 0-2 R^(4b), provided that R^(1d) forms    other than an N—S bond;-   R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl    substituted with 0-2 R^(4b), benzyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle    substituted with 0-2 R^(4b), and —(CH₂)_(r)-5-10 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O , and S(O)_(p) and substituted    with 0-2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl    substituted with 0-2 R^(4b), benzyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle    substituted with 0-2 R^(4b), and —(CH₂)_(r)-5-10 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0-2 R^(4b) and    consisting of: 0-1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy    substituted with 0-2 R^(4b), C₁₋₆ alkyl substituted with 0-2 R^(4b),    —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(4b), and    —(CH₂)_(r)-5-10 membered heterocycle consisting of: carbon atoms and    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,    C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(4b),    and —(CH₂)_(r)-5-10 membered heterocycle containing from 1-4    heteroatoms selected from the group consisting of N, O, and S(O)_(p)    and substituted with 0-2 R^(4b);-   R^(2d), at each occurrence, is selected from H, R^(4c), C₁₋₆ alkyl    substituted with 0-2 R^(4c), —(CR³R^(3a))_(r)—C₃₋₁₀ carbocycle    substituted with 0-2 R^(4c), and —(CR³R^(3a))_(r)-5-10 membered    heterocycle substituted with 0-2 R^(4c) and consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), provided that R^(2d) forms other than a N-halo,    N—C-halo, S(O)_(p)-halo, O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O,    O—N, O—S, or O—O moiety;-   alternatively, when two R^(2d)'s are attached to the same nitrogen    atom, then R^(2d) and R^(2d), together with the nitrogen atom to    which they are attached, combine to form a 5-10 membered saturated,    partially saturated or unsaturated ring substituted with 0-2 R^(4b)    and consisting of: 0-1 additional heteroatoms selected from the    group consisting of N, O, and S(O)_(p);-   R^(2e), at each occurrence, is selected from H, R^(4c), C₁₋₆ alkyl    substituted with 0-2 R^(4c), —(CR³R^(3a))_(r)—C₃₋₁₀ carbocycle    substituted with 0-2 R^(4c), and —(CR³R^(3a))_(r)-5-10 membered    heterocycle substituted with 0-2 R^(4c) and consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), provided that R^(2e) forms other than a C(O)-halo    or C(O)—S(O)_(p) moiety;-   R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl,    and phenyl;-   R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, benzyl, and phenyl;-   alternatively, R³ and R^(3a), together with the nitrogen atom to    which they are attached, combine to form a 5 or 6 membered    saturated, partially unsaturated, or unsaturated ring consisting of:    carbon atoms, the nitrogen atom to which R³ and R^(3a) are attached,    and 0-1 additional heteroatoms selected from the group consisting of    N, O, and S(O)_(p);-   R^(3b), at each occurrence, is selected from H, C₁₋₆ alkyl    substituted with 0-2 R^(1a), C₂₋₆ alkenyl substituted with 0-2    R^(1a), C₂₋₆ alkynyl substituted with 0-2 R^(1a), —(C₀₋₄ alkyl)-5-10    membered carbocycle substituted with 0-3 R^(1a), and —(C₀₋₄    alkyl)-5-10 membered heterocycle substituted with 0-3 R^(1a) and    consisting of: carbon atoms and 1-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p);-   R^(3c), at each occurrence, is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl,    and phenyl;-   R^(3d), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₁₋₄    alkyl-phenyl, and C(═O)R^(3c);-   R^(3g), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, —(CH₂)_(r)-3-6 membered carbocycle, and —(CH₂)_(r)-5-6    membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p);-   alternatively, when R³ and R^(3g) are attached to the same carbon    atom, they combine with the attached carbon atom to form a    cyclopropyl group;-   R⁴, at each occurrence, is selected from H, ═O, (CR³R^(3a))_(r)OR²,    (CR³R^(3a))_(r)F, (CR³R^(3a))_(r)Cl, (CR³R^(3a))_(r)Br,    (CR³R^(3a))_(r)I, C₁₋₄ alkyl, (CR³R^(3a)a)_(r)CN,    (CR³R^(3a))_(r)NO₂, (CR³R^(3a))_(r)NR²R^(2a),    (CR³R^(3a))_(r)C(O)R^(2c), (CR³R^(3a))_(r)NR²C(O)R^(2b),    (CR³R^(3a))_(r)C(O)NR²R^(2a), (CR³R^(3a))_(r)NR²C(O)NR²R^(2a), (CR    ³R^(3a))_(r)C(═NR²)NR²R^(2a), (CR³R^(3a))_(r)C(═NS(O)₂R⁵)NR²R^(2a),    (CR³R^(3a))_(r)NR²C(═NR²)NR²R^(2a),    (CR³R^(3a))_(r)C(O)NR²C(═NR²)NR²R^(2a), (CR³R^(3a))_(r)SO₂NR²R^(2a),    (CR³R^(3a))_(r)NR²SO₂NR²R^(2a), (CR³R^(3a))_(r)NR²SO2—C₁₋₄ alkyl,    (CR³R^(3a))_(r)NR²SO₂R⁵, (CR³R^(3a))_(r)S(O)_(p)R^(5a),    (CR³R^(3a))_(r)(CF₂)_(r)CF₃, NHCH₂R^(1b), OCH₂R^(1b), SCH₂R^(1b),    NH(CH₂)₂(CH₂)_(t)R^(1b), O(CH₂)₂(CH₂)_(t)R^(1b),    S(CH₂)₂(CH₂)_(t)R^(1b), (CR³R^(3a))_(r)-5-6 membered carbocycle    substituted with 0-1 R⁵, and a (CR³R^(3a))_(r)-5-6 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-1 R⁵;-   R^(4a) is selected from C₁₋₆ alkyl substituted with 0-2 R^(4c), C₂₋₆    alkenyl substituted with 0-2 R^(4c), C₂₋₆ alkynyl substituted with    0-2 R^(4c), —(CR³R^(3g))_(r)—C₅₋₁₀ membered carbocycle substituted    with 0-3 R^(4c), —(CR³R^(3g))_(r)-5-10 membered heterocycle    substituted with 0-3-R^(4c) and consisting of: carbon atoms and 1-4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), (CR³R^(3g))_(r)CN,    (CR³R^(3g))_(r)C(═NR^(2d))NR^(2d)R^(2d),    (CR³R^(3g))_(r)NR^(2d)C(═NR^(2d))NR^(2d)R^(2d),    (CR³R^(3g))_(r)NR^(2d)C(R^(2e))(═NR^(2d)),    (CR³R^(3g))_(r)NR^(2d)R^(2d), (CR³R^(3g))_(r)N(→O)R^(2d)R^(2d),    (CR³R^(3g))_(r)OR^(2d), (CR³R^(3g))_(r)—NR^(2d)C(O)R^(2e),    (CR³R^(3g))_(r)—C(O)R^(2e), (CR³R^(3g))_(r)—OC(O)R^(2e),    (CR³R^(3g))_(r)—C(O)NR^(2d)R^(2d), (CR³R^(3g))_(r)—C(O)OR^(2d),    (CR³R^(3g))_(r)—NR^(2d)C(O)NR^(2d)R^(2d),    (CR³R^(3g))_(r)—OC(O)NR^(2d)R^(2d),    (CR³R^(3g))_(r)—NR^(2d)C(O)OR^(2d),    (CR³R^(3g))_(r)—SO₂NR^(2d)R^(2d),    (CR³R^(3g))_(r)—NR^(2d)SO₂NR^(2d)R^(2d),    (CR³R^(3g))_(r)—C(O)NR^(2d)SO₂R^(2d),    (CR³R^(3g))_(r)—NR^(2d)SO₂R^(2d), and    (CR³R^(3g))_(r)—S(O)_(p)R^(2d), provided that S(O)_(p)R^(2d) forms    other than S(O)₂H or S(O)H and further provided that R^(4a) is other    than a hydroxamic acid;-   R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³,    (CH₂)_(r)F, (CH₂)_(r)Cl, (CH₂)_(r)Br, (CH₂)_(r)I, C₁₋₄ alkyl,    (CH₂)_(r)CN, (CH₂)_(r)NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,    (CH₂)_(r)C(O)OR^(3c), (CH₂)_(r)NR³C(O)R^(3a),    (CH₂)_(r)—C(O)NR³R^(3a), (CH₂)_(r)NR³C(O)NR³R^(3a),    (CH₂)_(r)—C(═NR³)NR³R^(3a), (CH₂)_(r)NR³C(═NR³)NR³R^(3a),    (CH₂)_(r)SO₂NR³R^(3a), (CH₂)_(r)NR³SO₂NR³R^(3a),    (CH₂)_(r)NR³SO₂—C₁₋₄ alkyl, (CH₂)_(r)NR³SO₂CF₃,    (CH₂)_(r)NR³SO₂-phenyl, (CH₂)_(r)S(O)_(p)CF₃, (CH₂)_(r)S(O)_(p)—C₁₋₄    alkyl, (CH₂)_(r)S(O)_(p)-phenyl, and (CH₂)_(r)(CF₂)_(r)CF₃;-   R^(4c), at each occurrence, is selected from ═O, (CR³R^(3a))_(r)OR²,    (CR³R^(3a))_(r)F, (CR³R^(3a))_(r)Br, (CR³R^(3a))_(r)Cl,    (CR³R^(3a))_(r)CF₃, C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CR³R^(3a))_(r)CN, (CR³R^(3a))_(r)NO₂, (CR³R^(3a))_(r)NR²R^(2a),    (CR³R^(3a))_(r)N(→O)R²R^(2a), (CR³R^(3a))_(r)C(O)R^(2c),    (CR³R^(3a))_(r)NR²C(O)R^(2b), (CR³R^(3a))_(r)C(O)NR²R^(2a),    (CR³R^(3a))_(r)N═CHOR³, (CR³R^(3a))_(r)C(O)NR²(CH₂)₂NR²R^(2a),    (CR³R^(3a))_(r)NR²C(O)NR²R^(2a), (CR³R^(3a))_(r)C(═NR²)NR²R^(2a),    (CR³R^(3a))_(r)NR²C(═NR²)NR²R^(2a), (CR³R^(3a))_(r)SO₂NR²R^(2a),    (CR³R^(3a))_(r)NR²SO₂NR²R^(2a), (CR³R^(3a))_(r)C(O)NR²SO₂—C₁₋₄    alkyl, (CR³R^(3a))_(r)NR²SO₂R^(5a), (CR³R^(3a))_(r)C(O)NR²SO₂R^(5a),    (CR³R^(3a))_(r)S(O)_(p)R^(5a), (CF₂)_(r)CF₃, (CR³R^(3a))_(r)C₃₋₁₀    carbocycle substituted with 0-2 R^(4b), and (CR³R^(3a))_(r)4-10    membered heterocycle substituted with 0-2 R^(4b) and consisting of    carbon atoms and from 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R⁵, at each occurrence, is selected from H, C₁₋₆ alkyl, ═O,    (CH₂)_(r)OR³, F, Cl, Br, I, —CN, NO₂, (CH₂)_(r)NR³R^(3a),    (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c), (CH₂)_(r)NR³C(O)R^(3a),    (CH₂)_(r)C(O)NR³R^(3a), (CH₂)_(r)NR³C(O)NR³R^(3a),    (CH₂)_(r)CH(═NOR^(3d)), (CH₂)_(r)C(═NR³)NR³R^(3a),    (CH₂)_(r)NR³C(═NR³)NR³R^(3a), (CH₂)_(r)SO₂NR³R^(3a),    (CH₂)_(r)NR³SO₂NR³R^(3a), (CH₂)_(r)NR³SO₂—C₁₋₄ alkyl,    (CH₂)_(r)NR³SO₂CF₃, (CH₂)_(r)NR³SO₂-phenyl, (CH₂)_(r)S(O)_(p)CF3,    (CH₂)_(r)S(O)_(p)—C₁₋₄ alkyl, (CH₂)_(r)S(O)_(p)-phenyl,    (CF₂)_(r)CF₃, phenyl substituted with 0-2 R⁶, naphthyl substituted    with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;-   R^(5a), at each occurrence, is selected from C₁₋₆ alkyl,    (CH₂)_(r)OR³, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,    (CH₂)_(r)C(O)OR^(3c), (CH₂)_(r)NR³C(O)R^(3a),    (CH₂)_(r)C(O)NR³R^(3a), (CF₂)_(r)CF₃, phenyl substituted with 0-2    R⁶, naphthyl substituted with 0-2 R⁶, and benzyl substituted with    0-2 R⁶, provided that R^(5a) does not form a S—N or S(O)_(p)—C(O)    bond;-   R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo,    C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b),    NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂,    SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂—C₁₋₄ alkyl;-   R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆    alkyl-C(O)—, C₁₋₆ alkyl-O—, (CH₂)_(n)-phenyl, C₁₋₄ alkyl-OC(O)—,    C₆₋₁₀ aryl-O—, C₆₋₁₀ aryl-OC(O)—, C₆₋₁₀ aryl-CH₂—C(O)—, C₁₋₄    alkyl-C(O)O—C₁₋₄ alkyl-OC(O)—, C₆₋₁₀ aryl-C(O)O—C₁₋₄ alkyl-OC(O)—,    C₁₋₆ alkyl-NH₂—C(O)—, phenyl-NH₂—C(O)—, and phenyl C₁₋₄ alkyl-C(O)—;-   R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl, and    (CH₂)_(n)-phenyl; alternatively, R⁷ and R⁸, when attached to the    same nitrogen, combine to form a 5-10 membered heterocyclic ring    consisting of carbon atoms and 0-2 additional heteroatoms selected    from the group consisting of N, O, and S(O)_(p);-   R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl, and    (CH₂)_(n)-phenyl;-   n, at each occurrence, is selected from 0, 1, 2, and 3;-   p, at each occurrence, is selected from 0, 1, and 2;-   r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;-   r1, at each occurrence, is selected from 1, 2, 3, 4, 5, and 6; and,-   t, at each occurrence, is selected from 0, 1, 2, and 3.

In another embodiment, the present invention provides a novel compound,wherein:

-   the central lactam ring is substituted with 0-1 R^(1a);-   G is a group of formula IIa or IIb:-   ring D, including the two atoms of ring E to which it is attached,    is a 5-6 membered ring consisting of: carbon atoms and 0-2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p);-   ring D is substituted with 0-2 R and there are 0-3 ring double    bonds;-   E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and    pyridazinyl, and is substituted with 1-2 R;-   alternatively, ring D is absent, and ring E is selected from phenyl,    pyridyl, pyrimidyl, and thienyl, and ring E is substituted with 1-2    R;-   alternatively, ring D is absent, ring E is selected from phenyl,    pyridyl, and thienyl, and ring E is substituted with a 5 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), wherein the 5    membered heterocycle is substituted with 0-1 carbonyls and 1-2 R and    has 0-3 ring double bonds;-   R is selected from H, C₁₋₄ alkyl, F, Cl, OH, OCH₃, OCH₂CH₃,    OCH(CH₃)₂, CN, C(═NH)NH₂, NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂,    C(═NH)NH₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃ alkyl)₂,    (CR⁸R⁹)_(t)NR⁷R⁸, C(O)NR⁷R⁸, CH₂C(O)NR⁷R⁸, S(O)_(p)NR⁷R⁸,    CH₂S(O)_(p)NR⁷R⁸, and OCF₃;-   alternatively, when 2 R groups are attached to adjacent atoms, they    combine to form methylenedioxy or ethylenedioxy;-   G₁ is selected from H, (CR³R^(3a))C(O)R², (CR³R^(3a))NR²R^(2a),    (CR³R^(3a))OR², (CR³R^(3a))S(O)_(p)R², (CR³R^(3a))NR²C(O)R²,    (CR³R^(3a))NR²C(O)NR²R^(2a), (CR³R^(3a))NR²C(O)OR²,    (CR³R^(3a))S(O)₂NR²R^(2a), (CR³R^(3a))NR²S(O)₂NR²R^(2a),    (CR³R^(3a))OC(O)R², (CR³R^(3a))C(O)OR², (CR³R^(3a))C(O)NR²R^(2a),    (CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))OR²,    (CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))(CR³R^(3a))OR²,    (CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))NR²R^(2a),    (CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))(CR³R^(3a))NR²R^(2a),    (CR³R^(3a))C(O)NR²(CR³R^(3a))C(O)NR²R^(2a),    (CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))C(O)NR²R^(2a),    (CR³R^(3a))C(O)NR²(CR³R^(3a))C(O)OR²,    (CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))C(O)OR², C₁₋₆ alkyl    substituted with 0-1 R^(1a), C₂₋₆ alkenyl substituted with 0-1    R^(1a), C₂₋₆ alkynyl substituted with 0-1 R^(1a),    (CR³R^(3a))₀₋₄—C₃₋₁₀ carbocycle substituted with 0-1 R^(1a), and    (CR³R^(3a))₀₋₄-5-12 membered heterocycle consisting of: carbon atoms    and 1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-1 R^(1a);-   A is selected from:    -   C₅₋₁₀ carbocycle substituted with 0-2 R⁴, and    -   5-10 membered heterocycle consisting of: carbon atoms and 1-4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p) and substituted with 0-2 R⁴;    -   provided that A is other than a dihydro-benzopyran;-   B is selected from N(B¹)C(O)C(R³R^(3g))NB²B³,    N(B¹)C(O)C(R³R^(3g))C(R³R^(3g))NB²B³,    and    provided that the central lactam ring and B are attached to    different atoms on A and that the A-X—N moiety forms other than a    N—N—N group;-   B¹ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —(CH₂)₀₋₁—C₃₋₇    carbocycle substituted with 0-2 R^(4b), and —(CH₂)₀₋₁-5-6 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-2 R^(4b);-   B² is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, NR^(2d)R^(2d),    CH₂—NR^(2d)R^(2d), CH₂CH₂—NR^(2d)R^(2d), C(O)R^(2e),    C(O)NR^(2d)R^(2d)SO₂NR^(2d)R^(2d), and S(O)_(p)R^(5a);-   B³ is selected from H, C₁₋₆ alkyl substituted with 0-1 R^(4c),    —(CH₂)₀₋₁-3-6 membered carbocycle substituted with 0-1 R⁵, and a    —(CH₂)₀₋₁-5-6 membered heterocycle consisting of: carbon atoms and    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-1 R⁵;-   ring Q is a 4-7 membered lactam consisting of, in addition to the    amide group shown, carbon atoms and 0-2 heteroatoms selected from    NR^(4c), O, S, S(O), and S(O)₂, wherein:    -   0-2 double bonds are present within the ring and the ring is        substituted with 0-2 R^(4a);-   alternatively, ring Q is a 4-7 membered lactam to which another ring    is fused, wherein:    -   the lactam consists of, in addition to the shown amide group,        carbon atoms and 0-2 heteroatoms selected from NR^(4c), O, S,        S(O), and S(O)₂ and 0-1 double bonds are present within the        ring;    -   the fusion ring is phenyl or a 5-6 membered heteroaromatic        consisting of carbon atoms and 0-2 NR^(4c), O, and S;    -   ring Q, which includes the lactam ring and the fusion ring, is        substituted with 0-3 R^(4a);-   ring Q¹ is selected from CY¹Y² , a C₃₋₇ monocyclic carbocycle, and a    3-7 membered monocyclic heterocycle, wherein the carbocycle or    heterocycle consists of: carbon atoms and 0-2 heteroatoms selected    from N, O, and S(O)_(p), the carbocycle or heterocycle further    comprises 0-2 double bonds and 0-2 carbonyl groups, and the    carbocycle or heterocycle is substituted with 0-2 R⁴;-   X is absent or is selected from —(CR²R^(2a))₁₋₄—, —C(O)—,    —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)₂—, —S(O)₂CR²R^(2a)—,    —CR²R^(2a)S(O)₂—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²C(O)—, —C(O)NR²—, NR²,    —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —OCR²R^(2a)—, and —CR²R^(2a)O—;-   Y¹ and Y² are independently C₁₋₃ alkyl substituted with 0-1 R⁴;-   R^(1a), at each occurrence, is selected from H,    —(CR³R^(3a))_(r)—R^(1b), —(CR³R^(3a))_(r)—O—(CR³R^(3a))_(r)—R^(1b),    —C₂₋₆ alkenylene-R^(1b), —C₂₋₆ alkynylene-R^(1b),    —(CR³R^(3a))_(r)—C(═NR^(1b))NR³R^(1b), NR³(CR³R^(3a))_(t)R^(1c),    O(CR³R^(3a))_(t)R^(1c), (CR³R^(3a))_(r)SCR³R^(3a)R^(1c),    (CR³R^(3a))_(r)NR³(CR³R^(3a))_(r)R^(1b),    (CR³R^(3a))_(r)C(O)NR²(CR³R^(3a))_(r)R^(1b),    CO₂(CR³R^(3a))_(t)R^(1b), O(CR³R^(3a))_(t)R^(1b),    S(O)_(p)(CR³R^(3a))_(r)R^(1d), O(CR³R^(3a))_(r)R^(1d),    NR³(CR³R^(3a))_(r)R^(1d), OC(O)NR³(CR³R^(3a))_(r)R^(1d),    NR³C(O)NR³(CR³R^(3a))_(r)R^(1d), NR³C(O)O(CR³R^(3a))_(r)R^(1d), and    NR³C(O)(CR³R^(3a))_(r)R^(1d), provided that R^(1a) forms other than    an N-halo, N—S, O—O, or N—CN bond;-   alternatively, when two R^(1a) groups are attached to the same    carbon atom, together with the carbon atom to which they are    attached they form a 3-10 membered carbocyclic or heterocyclic ring    consisting of: carbon atoms and 0-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p), this ring being substituted    with 0-2 R⁴ and 0-3 ring double bonds;-   R^(1b) is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, F, Cl,    Br, I, —CN, —CHO, CF₃, (CR³R^(3a))_(r)OR², NR²R^(2a), C(O)R^(2b),    CO₂R^(2b), OC(O)R², C₂R^(2a), S(O)_(p)R², NR²(CH₂)_(r)OR²,    NR²C(O)R^(2b), NR²C(O)NR²R^(2a), NR²C(O)₂R^(2a), OC(O)NR²R^(2a),    C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂NR²R^(2a),    NR²SO₂R², C(O)NR²SO₂R², SO₂NR²C(O)R², C₃₋₁₀ carbocycle substituted    with 0-2 R⁴, and 4-10 membered heterocycle consisting of carbon    atoms and from 1-4 heteroatoms selected from the group consisting of    N, O, and S(O)_(p) and substituted with 0-2 R⁴, provided that R^(1b)    forms other than an O—O, N-halo, N—S, or N—CN bond;-   R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),    S(O)R², S(O)₂R², and SO₂NR²R^(2a);-   R², at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂, benzyl,    C₅₋₆ carbocycle substituted with 0-2 R^(4b), a C₅₋₆ carbocyclic-CH₂    group substituted with 0-2 R^(4b), a 5-6 membered heterocycle    consisting of: carbon atoms and 1-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p) and substituted with 0-2    R^(4b), and a 5-6 membered heterocycle-CH₂ group consisting of:    carbon atoms and 1-4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p) and substituted with 0-2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂, benzyl,    C₅₋₆ carbocycle substituted with 0-2 R^(4b), and 5-6 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0-2 R^(4b)and    consisting of: 0-1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0-2    R^(4b), and 5-6 membered heterocycle consisting of: carbon atoms and    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy,    CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0-2    R^(4b), and 5-6 membered heterocycle containing from 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) and    substituted with 0-2 R^(4b);-   R^(2d), at each occurrence, is selected from H, R^(4c), C₁₋₄ alkyl    substituted with 0-2 R^(4c), —(CR³R^(3a))_(r)—C₃₋₆ carbocycle    substituted with 0-2 R^(4c), and —(CR³R^(3a))_(r)-5-6 membered    heterocycle substituted with 0-2 R^(4c) and consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), provided that R^(2d) forms other than a N-halo,    N—C-halo, S(O)_(p)-halo, O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O,    O—N, O—S, or O—O moiety;-   alternatively, when two R ^(2d)'s are attached to the same nitrogen    atom, then R^(2d) and R^(2d), together with the nitrogen atom to    which they are attached, combine to form a 5 or 6 membered    saturated, partially saturated or unsaturated ring substituted with    0-2 R^(4b) and consisting of: 0-1 additional heteroatoms selected    from the group consisting of N, O, and S(O)_(p);-   R^(2e), at each occurrence, is selected from H, R^(4c), C₁₋₄ alkyl    substituted with 0-2 R^(4c), —(CR³R^(3a))_(r)—C₃₋₆ carbocycle    substituted with 0-2 R^(4c), and —(CR³R^(3a))_(r)-5-6 membered    heterocycle substituted with 0-2 R^(4c) and consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), provided that R^(2e) forms other than a C(O)-halo    or C(O)—S(O)_(p) moiety;-   R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, benzyl, and phenyl;-   R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, benzyl, and phenyl;-   alternatively, R³ and R^(3a), together with the nitrogen atom to    which they are attached, combine to form a 5 or 6 membered    saturated, partially unsaturated, or unsaturated ring consisting of:    carbon atoms and the nitrogen atom to which R³ and R^(3a) are    attached;-   R^(3c), at each occurrence, is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, benzyl, and phenyl;-   R^(3d), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂-phenyl, CH₂CH₂-phenyl, and C(═O)R^(3c);-   R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR²,    (CH₂)₂OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, NR²R^(2a),    CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R^(5a), CF₃, CF₂CF₃, 5-6    membered carbocycle substituted with 0-1 R⁵, and a 5-6 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-1 R⁵;-   R⁴, at each occurrence, is selected from H, ═O, OR², CH₂OR²,    (CH₂)₂OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, NR²R^(2a),    CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), NR²C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a),    S(O)_(p)R^(5a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, CF₃, CF₂CF₃, 5-6    membered carbocycle substituted with 0-1 R⁵, and a 5-6 membered    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0-1 R⁵;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a), C(O)R³,    CH₂—C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c), NR³C(O)R^(3a),    CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂C(O)NR³R^(3a), NR³C(O)NR³R^(3a),    CH₂NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), CH₂C(═NR³)NR³R^(3a),    NR³C(═NR³)NR³R^(3a), CH₂NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a),    CH₂SO₂NR³R^(3a), NR³SO₂NR³R^(3a), CH₂NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄    alkyl, CH₂NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, CH₂NR³SO₂CF₃, NR³SO₂-phenyl,    CH₂NR³SO₂-phenyl, S(O)_(p)CF₃, CH₂S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    CH₂S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, CH₂S(O)_(p)-phenyl, CF₃,    and CH₂—CF₃;-   R^(4c), at each occurrence, is selected from ═O, (CR³R^(3a))_(r)OR²,    (CR³R^(3a))_(r)F, (CR³R^(3a))_(r)Br, (CR³R^(3a))_(r)Cl,    (CR³R^(3a))_(r)CF₃, C₁₋₄ alkyl, C₂₋₃ alkenyl, C₂₋₃ alkynyl,    (CR³R^(3a))_(r)CN, (CR³R^(3a))_(r)NO₂, (CR³R^(3a))_(r)NR²R^(2a),    (CR³R^(3a))_(r)N(→O)R²R^(2a), (CR³R^(3a))_(r)C(O)R^(2c),    (CR³R^(3a))_(r)NR²C(O)R^(2b), (CR³R^(3a))_(r)C(O)NR²R^(2a),    (CR³R^(3a))_(r)NR²C(O)NR²R^(2a), (CR³R^(3a))_(r)SO₂NR²R^(2a),    (CR³R^(3a))_(r)NR²SO₂NR²R^(2a), (CR³R^(3a))_(r)NR²SO₂R^(5a),    (CR³R^(3a))_(r)C(O)NR²SO₂R^(5a), (CR³R^(3a))_(r)S(O)_(p)R^(5a),    (CF₂)_(r)CF₃, (CR³R^(3a))_(r)C₃₋₁₀ carbocycle substituted with 0-2    R^(4b), and (CR³R^(3a))_(r)5-10 membered heterocycle consisting of    carbon atoms and from 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b);-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,    C(CH₃)₃, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a),    C(O)R³, CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c), NR³C(O)R^(3a),    C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NOR^(3d)), C(═NR³)NR³R^(3a),    NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄    alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0-2 R⁶, naphthyl    substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶; and,-   R^(5a), at each occurrence, is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, OR³,    CH₂OR³, NR³R^(3a), CH₂NR³R^(3a), C(O)R³, CH₂C(O)R³, C(O)OR^(3c),    CH₂C(O)OR^(3c), NR³C(O)R^(3a), CH₂NR³C(O)R^(3a), C(O)NR³R^(3a),    CH₂C(O)NR³R^(3a), CF₃, CF₂CF₃, phenyl substituted with 0-2 R⁶,    naphthyl substituted with-0-2 R⁶, and benzyl substituted with 0-2    R⁶, provided that R^(5a) does not form a S—N or S(O)_(p)—C(O) bond;-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,    CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),    C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a),    C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and    NR²SO₂C₁₋₄ alkyl.

In another embodiment, the present invention provides a novel compound,wherein the compound is of formula Ib or Ic:

-   G is selected from the group:-   G₁ is selected from H, C₁₋₆ alkyl substituted with 0-1 R^(1a),    CH₂C(O)OR², CH₂C(O)NR²R^(2a), CH₂C(O)NR²CH₂CH₂OR²,    CH₂C(O)NR²CH₂CH₂NR²R^(2a), CH₂C(O)NR²CH₂C(O)NR²R^(2a),    CH₂C(O)NR²CH₂CH₂C(O)NR²R^(2a), CH₂C(O)NR²CH₂C(O)OR², and    CH₂C(O)NR²CH₂CH₂C(O)OR²;-   A is selected from one of the following carbocyclic and heterocyclic    groups which are substituted with 0-2 R⁴;    -   cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl,        pyrimidyl, furanyl, morpholinyl, thienyl, pyrrolyl,        pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,        pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,        1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,        1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,        1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,        1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolinyl,        indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl,        benzisoxazolyl, benzisothiazolyl, and isoindazolyl;-   B¹ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    —(CH₂)₀₋₁-C₅₋₆ carbocycle substituted with 0-2 R^(4b), and    —(CH₂)₀₋₁-5-6 membered heterocycle consisting of: carbon atoms and    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-2 R^(4b);-   B² is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, C(O)R^(2e),    C(O)NR^(2d)R^(2d), SO₂NR^(2d)R^(2d), and S(O)_(p)R^(5a);-   B³ is selected from H, C₁₋₆ alkyl substituted with 0-1 R^(4c),    —(CH₂)₀₋₁-3-6 membered carbocycle substituted with 0-1 R⁵, and a    —(CH₂)₀₋₁-5-6 membered heterocycle consisting of: carbon atoms and    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-1 R⁵;-   ring Q is a 5-7 membered lactam consisting of, in addition to the    amide group shown, carbon atoms and 0-2 heteroatoms selected from    NR^(4c), O, S, S(O), and S(O)₂, wherein:    -   0-2 double bonds are present within the ring and the ring is        substituted with 0-2 R^(4a);-   alternatively, ring Q is a 5-7 membered lactam to which another ring    is fused, wherein:    -   the lactam consists of, in addition to the shown amide group,        carbon atoms and 0-2 heteroatoms selected from NR^(4c), O, S,        S(O), and S(O)₂ and 0-1 double bonds are present within the        ring;    -   the fusion ring is phenyl or a 5-6 membered heteroaromatic        consisting of carbon atoms and 0-2 NR^(4c), O, and S;    -   ring Q, which includes the lactam ring and the fusion ring, is        substituted with 0-3 R^(4a);-   ring Q¹ is selected from CY¹Y², a C₃₋₆ monocyclic carbocycle, and    5-6 membered monocyclic heterocycle, wherein the carobocycle or    heterocycle consists of carbon atoms and 0-2 heteroatoms selected    from N, O, and S(O)_(p), the carbocycle or heterocycle further    comprises 0-1 double bonds and 0-1 carbonyl groups, and the    carbocycle or heterocycle is substituted with 0-2 R⁴;-   X is absent or is selected from —(CR²R^(2a))₁₋₂—, —C(O)—, —S(O)₂—,    —S(O)₂NR²—, —NR²S(O)₂—, —NR²C(O)—, —C(O)NR²—, NR², —NR²CR²R^(2a)—,    —CR²R^(2a)NR²—, O, —OCR²R^(2a)—, and —CR²R^(2a)O—;-   Y¹ and Y² are independently C₁₋₂ alkyl substituted with 0-1 R⁴;-   R^(1a), at each occurrence, is selected from H, —(CH₂)_(r)—R^(1b),    —(CH₂)_(r)—O—(CH₂)_(r)—R^(1b), —(CH₂)_(r)—C(═NR^(1b))NR³R^(1b),    NR³(CR³R^(3a))_(t)R^(1c), O(CR³R^(3a))R^(1c),    (CH₂)_(r)NR³(CH₂)_(r)R^(1b), (CH₂)_(r)C(O)NR²(CH₂)_(r)R^(1b),    CO₂(CH₂)_(t)R^(1b), O(CH₂)_(t)R^(1b), S(O)_(p)(CH₂)_(r)R^(1d),    O(CH₂)_(r)R^(1d), NR³(CH₂)_(r)R^(1d), OC(O)NR³(CH₂)_(r)R^(1d),    NR³C(O)NR³(CH₂)_(r)R^(1d), NR³C(O)O(CH₂)_(r)R^(1d), and    NR³C(O)(CH₂)_(r)R^(1d), provided that R^(1a) forms other than an    N-halo, N—S, O—O, or N—CN bond;-   alternatively, when two R^(1a) groups are attached to the same    carbon atom, together with the carbon atom to which they are    attached they form a 3-6 membered carbocyclic or heterocyclic ring    consisting of: carbon atoms and 0-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p), this ring being substituted    with 0-2 R⁴ and 0-3 ring double bonds;-   R^(1b) is selected from H, CH₃, CH₂CH₃, F, Cl, Br, —CN, —CHO, CF₃,    (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2b), CO₂R^(2b), OC(O)R², CO₂R^(2a),    S(O)_(p)R², NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)NR²R^(2a),    C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂R²,    C(O)NR²SO₂R², SO₂NR²C(O)R², C₃₋₁₀ carbocycle substituted with 0-2    R⁴, and 4-10 membered heterocycle consisting of carbon atoms and    from 1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-2 R⁴, provided that R^(1b) forms    other than an O—O, N-halo, N—S, or N—CN bond;-   R², at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂    NMe₂, phenyl substituted with 0-2 R^(4b), a benzyl substituted with    0-2 R^(4b), a 5-6 membered heterocycle-CH₂ group wherein said    heterocycle consists of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-2 R^(4b), and a 5-6 membered heterocycle consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p) and substituted with 0-2 R^(4b);-   R^(2a), at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂,    CH₂CH₂CH₂NMe₂, benzyl, phenyl substituted with 0-2 R^(4b), and 5-6    membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p) and    substituted with 0-2 R^(4b);-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0-2 R^(4b) and    consisting of: 0-1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substituted with 0-2    R^(4b), and 5-6 membered aromatic heterocycle consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p) and substituted with 0-2 R^(4b);-   R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0-2 R^(4b), and 5-6 membered aromatic    heterocycle containing from 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b);-   R^(2d), at each occurrence, is selected from H, R^(4c), C₁₋₄ alkyl    substituted with 0-2 R^(4c), C₃₋₆ carbocycle substituted with 0-2    R^(4c), —(CR³R^(3a))—C₃₋₆ carbocycle substituted with 0-2 R^(4c),    5-6 membered heterocycle substituted with 0-2 R^(4c) and consisting    of: carbon atoms and 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and —(CR³R^(3a))-5-6 membered    heterocycle substituted with 0-2 R^(4c) and consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), provided that R^(2d) forms other than a N-halo,    N—C-halo, S(O)_(p)-halo, O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O,    O—N, O—S, or O—O moiety;-   R^(2e), at each occurrence, is selected from H, R^(4c), C₁₋₄-alkyl    substituted with 0-2 R^(4c), C₃₋₆ carbocycle substituted with 0-2    R^(4c), —(CR³R^(3a))—C₃₋₆ carbocycle substituted with 0-2 R^(4c),    5-6 membered heterocycle substituted with 0-2 R^(4c) and consisting    of: carbon atoms and 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and —(CR³R^(3a))-5-6 membered    heterocycle substituted with 0-2 R^(4c) and consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), provided that R^(2e) forms other than a C(O)-halo    or C(O)—S(O)_(p) moiety;-   R⁴, at each occurrence, is selected from H, ═O, CH₂OR², (CH₂)₂OR²,    OR², F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,    CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR²R^(2a),    CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), NR²C(O)NR²R^(2a), SO₂NR²R^(2a), CF₃, and CF₂CF₃;-   R^(4a) is selected from —(CR³R^(3g))_(r)-5-6 membered carbocycle    substituted with 0-3 R^(4c), —(CR³R^(3g))_(r)-5-6 membered    heterocycle substituted with 0-3 R^(4c) and consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), (CR³R^(3g))_(r)NR^(2d)R^(2d),    (CR³R^(3g))_(r)N(→O)R^(2d)R^(2d), (CR³R^(3g))^(r)OR^(2d),    (CR³R^(3g))_(r)—NR^(2d)C(O)R^(2e), (CR³R^(3g))_(r)—C(O)R^(2e),    (CR³R^(3g))^(r)—OC(O)R^(2e), (CR³R^(3g))_(r)—C(O)NR^(2d)R^(2d),    (CR³R^(3g))_(r)—C(O)OR^(2d),    (CR³R^(3g))_(r)—NR^(2d)C(O)NR^(2d)R^(2d),    (CR³R^(3g))_(r)—NR^(2d)C(O)OR^(2d),    (CR³R^(3g))_(r)—SO₂NR^(2d)R^(2d), (CR³R^(3g))_(r)—NR^(2d)SO₂R^(2d),    and (CR³R^(3g))_(r)—S(O)_(p)R^(2d), provided that S(O)_(p)R^(2d)    forms other than S(O)₂H or S(O)H;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, CH₂—C(O)R³, C(O)OR^(3c), CH₂—C(O)OR^(3c),    NR³C(O)R^(3a), CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂—C(O)NR³R^(3a),    SO₂NR³R^(3a), CH₂SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, CH₂NR³SO₂—C₁₋₄    alkyl, NR³SO₂-phenyl, CH₂NR³SO₂-phenyl, S(O)_(p)CF₃, CH₂S(O)_(p)CF₃,    S(O)_(p)—C₁₋₄ alkyl, CH₂S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl,    CH₂S(O)_(p)-phenyl, and CF₃;-   R^(4c), at each occurrence, is selected from ═O, OR²,    (CR³R^(3a))OR², F, (CR³R^(3a))F, Br, (CR³R^(3a))Br, Cl,    (CR³R^(3a))Cl, CF₃, (CR³R^(3a))CF₃, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₄    alkyl, —CN, (CR³R^(3a))CN, NO₂, (CR³R^(3a))NO₂, NR²R^(2a),    (CR³R^(3a))NR²R^(2a), N(→O)R²R^(2a), (CR³R^(3a))N(→O)R²R^(2a),    C(O)R^(2c), (CR³R^(3a))C(O)R^(2c), NR²C(O)R^(2b),    (CR³R^(3a))NR²C(O)R^(2b), C(O)NR²R^(2a), (CR³R^(3a))C(O)NR²R^(2a),    NR²C(O)NR²R^(2a), (CR³R^(3a))NR²C(O)NR²R^(2a), SO₂NR²R^(2a),    (CR³R^(3a))SO₂NR²R^(2a), NR²SO₂NR²R^(2a),    (CR³R^(3a))NR²SO₂NR²R^(2a), NR²SO₂R^(5a), (CR³R^(3a))NR²SO₂R^(5a),    S(O)_(p)R^(5a), (CR³R^(3a))S(O)_(p)R^(5a), CF₃, CF₂CF₃, C₃₋₁₀    carbocycle substituted with 0-2 R^(4b), (CR³R^(3a))C₃₋₁₀ carbocycle    substituted with 0-2 R^(4b), 5-10 membered heterocycle consisting of    carbon atoms and from 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b),    and (CR³R^(3a))-5-10 membered heterocycle consisting of carbon atoms    and from 1-4 heteroatoms selected from the group consisting of N, O,    and S(O)_(p) and substituted with 0-2 R^(4b);-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c),    NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl,    NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0-2 R⁶, naphthyl    substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),    C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), SO₂NR²R^(2a), and    NR²SO₂C₁₋₄ alkyl.

In another embodiment, the present invention provides a novel compound,wherein:

-   G is selected from the group:-   G₁ is selected from H, C₁₋₄ alkyl substituted with 0-1 R^(1a),    CH₂C(O)OR², CH₂C(O)NR²R^(2a), CH₂C(O)NHCH₂CH₂OR², and    CH₂C(O)NHCH₂CH₂NR²R^(2a), CH₂C(O)OR², CH₂C(O)NR²R^(2a),    CH₂C(O)N(CH₃)CH₂CH₂OR², CH₂C(O)N(CH₃)CH₂CH₂NR²R^(2a),    CH₂C(O)NR²CH₂C(O)NR²R^(2a), CH₂C(O)NR²CH₂CH₂C(O)NR²R^(2a),    CH₂C(O)NR²CH₂C(O)OR², and CH₂C(O)NR²CH₂CH₂C(O)OR²;-   A is selected from one of the following carbocyclic and heterocyclic    groups which are substituted with 0-2 R⁴;    -   cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl,        pyriridyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl,        isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;-   B is selected from N(B¹)C(O)C(R³R^(3g))NB²B³,    provided that the central lactam ring and B are attached to    different atoms on A;-   B¹ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂;-   B² is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂;-   B³ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, C₂₋₅ alkyl    substituted with 1 R^(4c), —(CH₂)₀₋₁-3-6 membered carbocycle    substituted with 0-1 R⁵, and a —(CH₂)₀₋₁-5-6 membered heterocycle    consisting of: carbon atoms and 1-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p) and substituted with 0-1 R⁵;-   ring Q is a 6-7 membered lactam consisting of, in addition to the    amide group shown, carbon atoms and 0-1 heteroatoms selected from    NR^(4c), O, S, S(O), and S(O)₂, wherein:    -   0-2 double bonds are present within the ring and the ring is        substituted with 0-2 R^(4a);-   alternatively, ring Q is a 5-7 membered lactam to which another ring    is fused, wherein:    -   the lactam consists of, in addition to the shown amide group,        carbon atoms and 0-1 heteroatoms selected from NR^(4c), O, S(O),        and S(O)₂ and 0-1 double bonds are present within the ring;    -   the fusion ring is phenyl;    -   ring Q, which includes the lactam ring and the fusion ring, is        substituted with 0-2R^(4a);-   ring Q¹ is selected from C(CH₃)₂, C(CH₂CH₃)₂, cyclopropyl,    cyclobutyl, cyclopentyl, cyclopentanonyl, cyclohexyl,    cyclohexanonyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl,    piperidinonyl, tetrahydrofuranyl, and tetrahydropyranyl, and, when Y    is a ring, Y is substituted with 0-1 R⁴;-   R^(1a) is selected from H, R^(1b), C(CH₃)₂R^(1b), CH(CH₃)R^(1b),    CH₂R^(1b), CH₂CH₂R^(1b), CH₂OCH₂CH₂R^(1b), OCH₂CH₂R^(1b),    (CH₂)_(r)NR³CH₂CH₂R^(1b), NR³(CR³R^(3a))_(t)R^(1c),    O(CR³R^(3a))^(t)R^(1c), (CH₂)_(r)C(O)NR²(CH₂)_(r)R^(1b),    S(O)_(p)(CH₂)_(r)R^(1d), O(CH₂)_(r)R^(1d), NR³(CH₂)_(r)R^(1d) ,    OC(O)NR³(CH₂)_(r)R^(1d), NR³C(O)NR³(CH₂)_(r)R^(1d),    NR³C(O)O(CH₂)_(r)R^(1d), and NR³C(O)(CH₂)_(r)R^(1d), provided that    R^(1a) forms other than an N-halo, N—S, O—O, or N—CN bond;-   alternatively, when two R^(1a) groups are attached to the same    carbon atom, together with the carbon atom to which they are    attached they form a 3-10 membered carbocyclic or heterocyclic ring    consisting of: carbon atoms and 0-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p), this ring being substituted    with 0-2 R⁴ and 0-2 ring double bonds;-   R^(1b) is selected from H, CH₃, CH₂CH₃, F, Cl, Br, —CN, —CHO, CF₃,    (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2b), CO₂R^(2b), OC(O)R², CO₂R^(2a),    S(O)_(p)R², NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)NR²R^(2a),    C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂R²,    C(O)NR²SO₂R², SO₂NR²C(O)R², C₃₋₆ carbocycle substituted with 0-2 R⁴,    and 4-10 membered heterocycle consisting of carbon atoms and from    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-2 R⁴, provided that R^(1b) forms    other than an O—O, N-halo, N—S, or N—CN bond;-   R^(2a), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂,    CH₂CH₂CH₂NMe₂, and benzyl;-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0-1 R^(4b) and    consisting of: 0-1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0-1 R^(4b), and 5-6 membered aromatic    heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p) and substituted with    0-1 R^(4b);-   R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃,    OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl,    phenyl substituted with 0-1 R^(4b), and 5-6 membered aromatic    heterocycle containing from 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p) and substituted with 0-1 R^(4b);-   R^(2d), at each occurrence, is selected from H, R^(4c), C₁₋₄ alkyl    substituted with 0-2 R^(4c), C₃₋₆ carbocycle substituted with 0-2    R^(4c), —(CH₂)—C₃₋₆ carbocycle substituted with 0-2 R^(4c), 5-6    membered heterocycle substituted with 0-2 R^(4c)and consisting of:    carbon atoms and 1-4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and —(CH₂)-5-6 membered heterocycle    substituted with 0-2 R^(4c) and consisting of: carbon atoms and 1-4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), provided that R^(2d) forms other than a N-halo, N—C-halo,    S(O)_(p)—halo, O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O, O—N, O—S,    or O—O moiety;-   R^(2e) at each occurrence, is selected from H, R^(4c), C₁₋₄ alkyl    substituted with 0-2 R^(4c), C₃₋₆ carbocycle substituted with 0-2    R^(4c), —(CH₂)—C₃₋₆ carbocycle substituted with 0-2 R^(4c), 5-6    membered heterocycle substituted with 0-2 R^(4c) and consisting of:    carbon atoms and 1-4 heteroatoms selected from the group consisting    of N, O, and S(O)_(p), and —(CH₂)-5-6 membered heterocycle and    consisting of: carbon atoms and 1-4 heteroatoms-selected-from the    group consisting of N, O, and S(O)_(p), provided that R^(2e) forms    other than a C(O)-halo or C(O)—S(O)_(p) moiety;-   R⁴, at each occurrence, is selected from H, ═O, OH, OR², CH₂OR²,    (CH₂)₂OR², F, Br, Cl, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,    CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, NR²R^(2a),    CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),    C(O)NR²R^(2a), SO₂NR²R^(2a), CF₃, and CF₂CF₃;-   R^(4a) is selected from —(CR³R^(3g))_(r)-5-6 membered carbocycle    substituted with 0-3 R^(4c), —(CR³R^(3g))_(r)-5-6 membered    heterocycle substituted with 0-3 R^(4c) and consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p), (CR³R^(3g))_(r)NR^(2d)R^(2d),    (CR³R^(3g))_(r)N(→O)R^(2d)R^(2d), (CR³R^(3g))_(r)OR^(2d),    (CR³R^(3g))_(r)—C(O)NR^(2d)R^(2d),    (CR³R^(3g))_(r)—NR^(2d)C(O)R^(2e), (CR³R^(3g))_(r)—C(O)R^(2e),    (CR³R^(3g))^(r)—NR^(2d)C(O)NR^(2d)R^(2d),    (CR³R^(3g))_(r)—NR^(2d)C(O)OR^(2d),    (CR³R^(3g))_(r)—NR^(2d)SO₂R^(2d), and    (CR³R^(3g))_(r)—S(O)_(p)R^(2d), provided that S(O)_(p)R^(2d) forms    other than S(O)₂H or S(O)H;-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂—C¹⁻⁴ alkyl, NR³SO₂-phenyl, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, and CF₃;-   R^(4c), at each occurrence, is selected from ═O, OR², CH₂OR², F, Br,    Cl, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,    CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, C₂₋₃ alkenyl, C₂₋₃ alkynyl,    —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), N(→O)R²R^(2a), CH₂N(→O)R²R^(2a),    C(O)R^(2c), CH₂C(O)R^(2c), NR²C(O)R^(2b), CH₂NR²C(O)R^(2b),    C(O)NR²R^(2a), CH₂C(O)NR²R^(2a), SO₂NR²R^(2a), CH₂SO₂NR²R^(2a),    NR²SO₂R^(5a), CH₂NR²SO₂R^(5a), S(O)_(p)R^(5a), CH₂S(O)_(p)R^(5a),    CF₃, CF₂CF₃, C₃₋₆ carbocycle substituted with 0-2 R^(4b), (CH₂)C₃₋₆    carbocycle substituted with 0-2 R^(4b), 5-6 membered heterocycle    consisting of carbon atoms and from 1-4 heteroatoms selected from    the group consisting of N, O, and S(O)_(p) and substituted with 0-2    R^(4b), and (CH₂)-5-6 membered heterocycle consisting of carbon    atoms and from 1-4 heteroatoms selected from the group consisting of    N, O, and S(O)_(p) and substituted with 0-2 R^(4b);-   R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a),    CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),    SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂-phenyl, S(O)_(p)—C₁₋₄ alkyl,    S(O)_(p)-phenyl, CF₃, phenyl substituted with 0-2 R⁶, naphthyl    substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶; and,-   R⁶, at each occurrence, is selected from H, OH, OR², F, Cl, CH₃,    CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),    C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), and SO₂NR²R^(2a).

In another embodiment, the present invention provides a novel, wherein:

-   G is selected from:-   A is selected from one of the following carbocyclic and heterocyclic    groups which are substituted with 0-2 R⁴;    -   cyclohexyl, phenyl, pyridyl, and pyrimidyl;-   B is selected from the group    alternatively, B is selected from N(B¹)C(O)C(R³R^(3g))NB²B³ and-   B¹ is selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃;-   B² is selected from H, CH₃, and CH₂CH₃;-   B³ is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,    C(CH₃)₃, CH(CH₃)CH₂CH(CH₃)₂, CH₂CH₂OH, CH(CH₃)CH₂OH,    CH(phenyl)CH₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl, and    CH₂-cyclopropyl;-   ring Q¹ is selected from C(CH₃)₂, C(CH₂CH₃)₂, cyclopropyl,    cyclobutyl, cyclopentyl, 2-cyclopentanonyl, cyclohexyl,    2-cyclohexanonyl, pyrrolidinyl (attached to A and R^(4a)at the    2-position), pyrrolidinyl (attached to A and R^(4a)at the    3-position), 2-pyrrolidinonyl (attached to A and R^(4a) at the    3-position), piperidinyl (attached to A and R^(4a) at the    4-position), 4-piperdinonyl (attached to A and R^(4a) at the    3-position), tetrahydrofuranyl, and tetrahydropyranyl (attached to A    and R^(4a) at the 4-position);-   R^(1a) is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂(CH₃)₂, CF₃,    CH₂CF₃, OCH₃, CH₂OH, C(CH₃)₂OH, CH₂OCH₃, NH₂, CH₂NH₂, NHCH₃,    CH₂NHCH₃, N(CH₃)₂, CH₂N(CH₃)₂, C₂H, COCH₃, CO₂CH₃, CH₂CO₂CH₃,    NHCOCH₃, S(O)CH₃, CH₂S(O)CH₃, S(O)₂CH₃, CH₂S(O)₂CH₃, C(O)NH₂,    CH₂C(O)NH₂, SO₂NH₂, CH₂SO₂NH₂, NHSO₂CH₃, CH₂NHSO₂CH₃, NHSO₂NHCH₃,    NHSO₂N(CH₃)₂, NHCO₂R^(2a), NHC(O)NHR^(2a), CH₂OCH₂CH₂NR²R^(2a),    C(O)NR²R^(2a), CH₂CH₂OR², CH₂C(O)NR²CH₂CH₂OR²,    C(O)NHCH₂CH₂NR²R^(2a), CH₂C(O)NHCH₂CH₂NR²R^(2a),    C(O)NCH₃CH₂CH₂NR²R^(2a), CH₂C(O)NCH₃CH₂CH₂NR²R^(2a),    CH₂NHCH₂CH₂NR²R^(2a), CH₂N(CH₃)CH₂CH₂NR ²R^(2a), phenyl substituted    with 0-2 R^(4b), —CH₂-phenyl substituted with 0-2 R^(4b), 5-10    membered aromatic heterocycle consisting of carbon atoms and from    1-4 heteroatoms selected from the group consisting of N, O, and    S(O)_(p) and substituted with 0-2 R^(4b), and —CH₂-5-10 membered    aromatic heterocycle consisting of carbon atoms and from 1-4    heteroatoms selected from the group consisting of N, O, and S(O)_(p)    and substituted with 0-2 R^(4b), provided that R^(1a) forms other    than an N-halo, N—S, O—O, or N—CN bond;-   R², at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂, phenyl    substituted with 0-1 R^(4b), benzyl substituted with 0-1 R^(4b), 5    membered aromatic heterocycle-CH₂ group wherein the heterocycle    consists of: carbon atoms and 1-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p) and substituted with 0-1    R^(4b) and 5 membered aromatic heterocycle consisting of: carbon    atoms and 1-4 heteroatoms selected from the group consisting of N,    O, and S(O)_(p) and substituted with 0-1 R^(4b);-   R^(2a), at each occurrence, is selected from H, CH₃, and CH₂CH₃,    CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, and CH₂CH₂CH₂NMe₂,-   alternatively, R² and R^(2a), together with the atom to which they    are attached, combine to form a 5 or 6 membered saturated, partially    saturated or unsaturated ring substituted with 0-1 R^(4b) and    consisting of: 0-1 additional heteroatoms selected from the group    consisting of N, O, and S(O)_(p);-   R^(2b), at each occurrence, is selected from OCH₃, OCH₂CH₃, CH₃, and    CH₂CH₃;-   R^(2c), at each occurrence, is selected from OH, OCH₃, OCH₂CH₃, CH₃,    and CH₂CH₃;-   R^(2d), at each occurrence, is selected from H, C₁₋₄ alkyl    substituted with 0-1 R^(4c), C₃₋₆ cycloalkyl substituted with 0-2    R^(4c), phenyl substituted with 0-2 R^(4c), and a 5-6 membered    aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), provided    that R^(2d) forms other than a N-halo, N—C-halo, S(O)_(p)-halo,    O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O, O—N, O—S, or O—O moiety;-   R^(2e), at each occurrence, is selected from H, C₁₋₄ alkyl    substituted with 0-1 R^(4c), C₃₋₆ cycloalkyl substituted with 0-2    R^(4c), phenyl, substituted with 0-2 R^(4c), and 5-6 membered    aromatic heterocycle consisting of: carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), provided    that R^(2e) forms other than a C(O)-halo or C(O)—S(O)_(p) moiety;-   R^(4a) is selected from NR^(2d)R^(2d), CH₂NR^(2d)R^(2d),    N(→O)R^(2d)R^(2d), CH₂N(→O)R^(2d)R^(2d), CH₂OR^(2d), C(O)R^(2e),    C(O)NR^(2d)R^(2d), CH₂C(O)NR^(2d)R^(2d), NR^(2d)C(O)R^(2e),    CH₂NR^(2d)C(O)R^(2e), NR^(2d)C(O)NR^(2d)R^(2d),    CH₂NR^(2d)C(O)NR^(2d)R^(2d), NR^(2d)C(O)OR^(2d),    CH₂NR^(2d)C(O)OR^(2d), NR^(2d)SO₂R^(2d), CH₂NR^(2d)SO₂R^(2d),    S(O)_(p)R^(2d), CH₂S(O)_(p)R^(2d), 5-6 membered carbocycle    substituted with 0-2 R^(4c), —(CH₂)-5-6 membered carbocycle    substituted with 0-2 R^(4c), 5-6 membered heterocycle substituted    with 0-2 R^(4c) and consisting of: carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    —(CH₂)-5-6 membered heterocycle substituted with 0-2 R^(4c) and    consisting of: carbon atoms and 1-4 heteroatoms selected from the    group consisting of N, O, and S(O)_(p) provided that S(O)_(p)R^(2d)    forms other than S(O)₂H or S(O)H; and,-   R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,    Cl, CH₃, CH₂CH₃, NR³R^(3a), CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c),    NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂-phenyl, S(O)₂CH₃,    S(O)₂-phenyl, and CF₃; and,-   R^(4c)is selected from ═O, OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂,    CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH═CH₂, CH≡CH, CH₂OH, CH₂OCH₃,    CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃, CH₂OCH(CH₃)₂, F, Br, Cl, CF₃, NR²R^(2a),    CH₂NR²R^(2a), C(O)R^(2c), CH₂C(O)R^(2c), NR²C(O)R^(2b),    CH₂NR²C(O)R^(2b), C(O)NR²R^(2a), CH₂C(O)NR²R^(2a), SO₂NR²R^(2a),    CH₂SO₂NR²R^(2a), NR²SO₂R^(5a), CH₂NR²SO₂R^(5a), S(O)_(p)R^(5a), and    CH₂S(O)_(p)R^(5a).

In another embodiment, the present invention provides a novel compound,wherein the compound is selected from:

-   B is selected from:-   R^(2d), at each occurrence, is selected from H, CH₃, CH₂CH₃,    CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CH₂CH(CH₃)₂, CH₂CCH, CH₂CH₂OH,    CH₂C(O)NH₂, cyclopropyl, CH₂-cyclopropyl, cyclobutyl, cyclopentyl,    and thiazolyl;-   R^(2e), at each occurrence, is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,    CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CH₂CH(CH₃)₂, CH₂-cyclopropyl, cyclopropyl,    and cyclopentyl;-   R^(4a) is substituted with 0-2 R^(4c) and selected from morpholine,    1,1-dioxo-thiomorpholine, dihydropyridine, piperidine, piperazine,    pyrrolidine, imidazole, imidazoline, imidazolidine, oxazoline, and    thiazoline; and,-   R^(4c) is selected from ═O, OH, OCH₃, and CH₃.

In another embodiment, the present invention provides a novel compound,wherein the compound is of the formula:

In another embodiment, the present invention provides a novel compound,wherein the compound is selected from the group:

-   a) 6-Chloronaphthalene-2-sulfonic acid    {1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxopiperidin-3-yl}-amide;-   b) 6-Chloronaphthalene-2-sulfonic acid    {1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxopiperidin-3-yl}amide;-   c) 6-Chlorothieno[2,3-b]pyridine-2-sulfonic acid    {1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxopiperidin-3-yl}amide;-   d)    2-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide;-   e)    (R)-2-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide;-   f)    (S)-2-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide;-   g)    2-((6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}-amino)-N-methylacetamide;-   h)    2-((6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}-amino)-N-(2-dimethylaminoethyl)-N-methylacetamide;-   i) 6-Chloronaphthalene-2-sulfonic acid    {1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}amide;-   j) 6-Chlorothieno[2,3-b]pyridine-2-sulfonic acid    {1-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxopiperidin-3-yl}amide; and,-   k)    2-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide;-   l)    2-{(6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxopiperidin-3-yl]-amino}-N-methyl-N-(1-methylpiperidin-4-yl)-acetamide;-   m) 6-Chloro-naphthalene-2-sulfonic    acid)-{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxo-piperidin-3-yl]-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;-   n) 6-Chloronaphthalene-2-sulfonic    acid)-{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxopiperidin-3-yl]-(2-morpholin-4-yl-2-oxoethyl)amide;-   o)    2-{(6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxopiperidin-3-yl]-amino}-N-methyl-N-(1-methylpiperidin-4-yl)-acetamide;-   p) 6-Chlorothieno[2,3-b]pyridine-2-sulfonic    acid)-{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxo-piperidin-3-yl]-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;-   q) 6-Chlorothieno[2,3-b]pyridine-2-sulfonic    acid)-{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxopiperidin-3-yl]-(2-morpholin-4-yl-2-oxoethyl)amide;    and-   r)    2-((6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}-amino)-N,N-dimethylacetamide;-   s)    N-{4-[3-(6-Chloro-naphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-2-dimethylamino-N-methyl-acetamide;-   t)    N-{4-[3-(6-Chloro-naphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-N-methyl-2-pyrrolidin-1-yl-acetamide;-   u)    N-{4-[3-(6-Chloro-naphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-2-dimethylamino-N-methylacetamide;-   v)    N-{4-[3-(6-Chloro-thieno[2,3-b]pyridine-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-2-dimethylamino-N-methyl-acetamide;-   w) 6-Chloro-naphthalene-2-sulfonic acid    methyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]    -piperidin-3-yl}-amide;-   x) 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic acid    methyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide;-   y) 6-Chloro-naphthalene-2-sulfonic acid    ethyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide;-   z) 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic acid    ethyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide;-   aa)    2-((6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide;-   bb) 6-Chloro-naphthalene-2-sulfonic acid    cyanomethyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide;-   cc) 6-Chloro-naphthalene-2-sulfonic acid    {2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-thiazol-4-yl    methyl-amide;-   dd) 6-Chloro-naphthalene-2-sulfonic acid    {2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-pyridin-3-yl    methyl-amide;-   ee) 6-Chloro-naphthalene-2-sulfonic acid    {2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-pyridin-2-yl    methyl-amide;-   ff) 6-Chloro-naphthalene-2-sulfonic acid    {2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-pyridin-4-yl    methyl-amide; gg)    2-((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-N-methyl-acetamide;-   hh)    2-((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide;-   ii) 6-Chloro-naphthalene-2-sulfonic acid (2-methyl-thiazol-4-yl    methyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide;-   jj)    4-Methoxy-N-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-benzenesulfonamide;-   kk) 5-Chloro-thiophene-2-sulfonic acid    {2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide;-   ll)    3-Chloro-N-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-benzenesulfonamide;-   mm)    ((4-Methoxy-benzenesulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl    }-amino)-acetic acid methyl ester; nn)    ((5-Chloro-thiophene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetic    acid methyl ester;-   oo)    2-((4-Methoxy-benzenesulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide;-   pp)    ((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetic    acid tert-butyl ester;-   qq)    2-((5-Chloro-thiophene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide;-   rr)    ((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetic    acid;-   ss) 5-Chloro-thieno[3,2-b]pyridine-2-sulfonic acid    {2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide;-   tt) 5-Chloro-[2,2]bithiophenyl-5-sulfonic acid    {2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide;-   uu)    2-((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-N-(2-hydroxy-ethyl)-acetamide;-   vv)    N-Carbamoylmethyl-2-((6-chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide;-   ww) 6-Chloro-naphthalene-2-sulfonic acid    {2-oxo-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-pyrrolidin-3-yl}-amide;-   xx) 6-Chloro-naphthalene-2-sulfonic acid    {2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-pyrrolidin-3-yl}-amide;-   yy) 6-Chloro-naphthalene-2-sulfonic acid    {2-oxo-1-[4-(1-pyrrolidin-1-yl    methyl-cyclopropyl)-phenyl]-piperidin-3-yl}-amide;-   zz) 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic acid    {2-oxo-1-[4-(1-pyrrolidin-1-yl    methyl-cyclopropyl)-phenyl]-piperidin-3-yl}-amide;-   aaa) ((5    -Chloro-[2,2]bithiophenyl-5-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetic    acid methyl ester;-   bbb) ((5-Chloro-thieno[3,    2-b]pyridine-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetic    acid methyl ester;-   ccc)    2-((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetic    acid methyl ester;-   ddd)    2-((6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetic    acid methyl ester;    or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel compound,wherein the compound is selected from the group:

-   a)    2-{(6-Chloronaphthalene-2-sulfonyl)-[1-(3-fluoro-2′-methanesulfonylbiphenyl-4-yl)-2-oxopiperidin-3-yl]-amino}-N-methyl-N-(1-methylpiperidin-4-yl)-acetamide;-   b) 6-Chloro-naphthalene-2-sulfonic acid    [1-(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-2-oxo-piperidin-3-yl]-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;-   c) 6-Chloronaphthalene-2-sulfonic acid    [1-(3-fluoro-2′-methanesulfonylbiphenyl-4-yl)-2-oxopiperidin-3-yl]-(2-morpholin-4-yl-2-oxoethyl)amide;-   d)    2-{(6-Chloronaphthalene-2-sulfonyl)-[1-(3-fluoro-2′-methanesulfonylbiphenyl-4-yl)-2-oxopiperidin-3-yl]-amino}-N-(2-hydroxyethyl)-N-methylacetamide;-   e) 6-Chloro-naphthalene-2-sulfonic acid    [1-(3-fluoro-2′-methanesulfonylbiphenyl-4-yl)-2-oxopiperidin-3-yl]-(3-hydroxy-propyl)amide;-   f) 6-Chloronaphthalene-2-sulfonic acid    {1-[4-(2-dimethylaminomethylimidazol-1-yl)-2-fluorophenyl]-2-oxopiperidin-3-yl}amide;-   g) 6-chlorothieno[2,3-b]pyridine-2-sulfonic acid    {1-[4-(2-dimethylaminomethylimidazol-1-yl)-2-fluorophenyl]-2-oxopiperidin-3-yl}amide;-   h) 5-chlorothieno[3,2-b]pyridine-2-sulfonic acid    {1-[4-(2-dimethylaminomethylimidazol-1-yl)-2-fluorophenyl]-2-oxopiperidin-3-yl}amide;-   i) 5-chlorobenzothienyl-2-sulfonic acid    {1-[4-(2-dimethylaminomethylimidazol-1-yl)-2-fluorophenyl]-2-oxopiperidin-3-yl}amide;-   j) 6-Chlorothieno[2,3-b]pyridine-2-sulfonic acid    {1-[4-(2-methylaminomethylimidazol-1-yl)-2-fluoro-phenyl]-2-oxo-piperidin-3-yl}amide;    and-   k)    ((6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-methylaminomethylimidazol-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)acetic    acid methyl ester;    or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides novelpharmaceutical compositions, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising:

-   -   (a) a first container;    -   (b) a pharmaceutical composition located within the first        container,        wherein the composition, comprises: a first therapeutic agent,        comprising: a compound of the present invention or a        pharmaceutically acceptable salt form thereof; and,    -   (c) a package insert stating that the pharmaceutical composition        can be used for the treatment of a thromboembolic disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising:

-   -   (d) a second container;        wherein components (a) and (b) are located within the second        container and component (c) is located within or outside of the        second container.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising:

-   -   (a) a first container;    -   (b) a pharmaceutical composition located within the first        container, wherein the composition, comprises: a first        therapeutic agent, comprising: a compound of the present        invention or a pharmaceutically acceptable salt form thereof;        and,    -   (c) a package insert stating that the pharmaceutical composition        can be used in combination with a second therapeutic agent to        treat a thromboembolic disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising:

-   -   (d) a second container;        wherein components (a) and (b) are located within the second        container and component (c) is located within or outside of the        second container.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides the use of acompound of the present invention as described above for the manufactureof a medicament for the treatment of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional more preferredembodiments. It is also to be understood that each individual element ofthe preferred embodiments is its own independent preferred embodiment.Furthermore, any element of an embodiment is meant to be combined withany and all other elements from any embodiment to describe an additionalembodiment.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. Tautomers of compounds shown or described herein areconsidered to be part of the present invention.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or1000 grams per mole. More preferably, the molecular weight is less thanabout 950 grams per mole. Even more preferably, the molecular weight isless than about 850 grams per mole. Still more preferably, the molecularweight is less than about 750 grams per mole.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

The present invention is also intended to include all stable oxides ofthiol and amino groups, even when not specifically written. When anamino group is listed as a substituent, the N-oxide derivative of theamino group is also included as a substituent. When a thiol group ispresent, the S-oxide and S,S-dioxide derivatives are also included.

When any variable (e.g., R⁶) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R⁶, then saidgroup may optionally be substituted with up to two R⁶ groups and R⁶ ateach occurrence is selected independently from the definition of R⁶.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to-cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. C₁₋₁₀ alkyl, is intended to includeC₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Examples ofalkyl include, but are not limited to, methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl”is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more halogen (for example —C_(v)F_(w),where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, butare not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl,and pentachloroethyl. “Alkoxy” represents an alkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. C₁₋₁₀ alkoxy, is intended to include C₁, C₂, C₃, C₄, C₅,C₆, C₇, C₈, C₉, and C₁₀ alkoxy groups. Examples of alkoxy include, butare not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intendedto include saturated ring groups, such as cyclopropyl, cyclobutyl, orcyclopentyl. C₃₋₇ cycloalkyl is intended to include C₃, C₄, C₅, C₆, andC₇ cycloalkyl groups. Alkenyl” is intended to include hydrocarbon chainsof either straight or branched configuration and one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₁₀ alkenyl is intended to include C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkenyl groups. “Alkynyl” isintended to include hydrocarbon chains of either straight or branchedconfiguration and one or more triple carbon-carbon bonds that may occurin any stable point along the chain, such as ethynyl and propynyl. C2-10Alkynyl is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adarnantyl, cycloctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, 10, 11, or 12-membered bicyclic or tricyclic heterocyclic ringwhich is saturated, partially unsaturated or unsaturated (aromatic), andwhich consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, O, and S andincluding any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized. The nitrogen atom may besubstituted or unsubstituted (i.e., N or NR wherein R is H or anothersubstituent, if defined). The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom that results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1. As used herein, the term “aromatic heterocyclic system”or “heteroaryl” is intended to mean a stable 5, 6, or 7-memberedmonocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclicaromatic ring which consists of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, O,and S. It is to be noted that total number of S and O atoms in thearomatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from 2-acetoxybenzoic,2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic,bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic,glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic,hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic,lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic,succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention may be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Substituted” is intended to indicate that one or more hydrogens on theatom indicated in the expression using “substituted” is replaced with aselection from the indicated group(s), provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O) group, then2 hydrogens on the atom are replaced.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention or an amount of the combination ofcompounds claimed effective to inhibit factor Xa. The combination ofcompounds is preferably a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984,22:27-55, occurs when the effect (in this case, inhibition of factor Xa)of the compounds when administered in combination is greater than theadditive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased antiviral effect, or some other beneficialeffect of the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. It will also berecognized that another major consideration in the planning of anysynthetic route in this field is the judicious choice of the protectinggroup used for protection of the reactive functional groups present inthe compounds described in this invention. An authoritative accountdescribing the many alternatives to the trained practitioner is Greeneand Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).All references cited herein are hereby incorporated in their entiretyherein by reference.

Compounds of this invention can be prepared as shown in Scheme 1,wherein an appropriately substituted 4-iodo or 4-bromoaniline 1a isconverted to 3-hydroxyvalerolactam 1b by a four-step sequence. Theaniline is reacted with tetrahydrofuryl-2-carbonyl chloride (preparedfrom the corresponding acid by treatment with oxalylchloride and DMF) inthe presence of a base such as triethylamine orN,N-dimethylaminopyridine to provide the amide. Treatment of this amidewith boron tribromide provides the ring-opened5-bromo-2-hydroxyvaleramide. The hydroxyl group is then protected as thecorresponding acetate by treatment with acetic anhydride, followed bycyclization to the 3-acetoxyvalerolactam by refluxing with a base suchas diisopropylamine in a suitable solvent such as N,N-dimethylacetamide. The acetate is subsequently hydrolyzed by treatmentwith potassium carbonate in methanol to give the 3-hydroxylactamintermediate 1b. Introduction of the B moiety is accomplished byUllmann, Goldberg, Buchwald copper catalyzed amidation depending on thenature of B, using methods known to one skilled in the art for thesetypes of couplings (see for example Lindley, Tetrahedron 1984, 40, 1433;Yin & Buchwald Organic Lett. 2000, 2, 1101; Klapers et al. JACS, 2001,123, 7727; Kiyomor, Madoux & Buchwald, Tet. Lett., 1999, 40 2657). Theresulting hydroxylactam 1c is then converted to the correspondingaminolactam 1d by a three step process. The hydroxyl group is eitherdisplaced by bromide, which can be accomplished either by treatment withcarbon tetrabromide and triphenylphosphine or by treatment withphosphorous tribromide in a solvent such as methylene chloride, oralternately it is converted to the mesylate by treatment withmesylchloride in the presence of a suitable base such as triethylamineor diisopropylethylamine. Displacement of either the bromide or mesylatewith azide is readily accomplished by heating in the presence of sodiumazide in a polar solvent such as N,N-dimethylformamide. The azide isthen reduced to amine 1d using any of a variety of methods known in theart for the transformation of azides to amines, for example, catalytichydrogenation over a Pd catalyst, Staudinger reduction withtriphenylphosphine or reduction with tin(II)chloride. Reaction of amine1d with an appropriate sulfonyl chloride provides sulfonamidederivatives 1e, which can be further derivatized by alkylation on thesulfonamide nitrogen via treatment with an alkyl bromide in the presenceof a suitable base such as potassium carbonate to provide compounds ofthis invention of formula 1f.

Compounds of this invention with R³ groups specifically derived from anacetic acid substituent are prepared as outlined in Scheme 2. Treatmentof sulfonamide derivatives, 1e, with an ester of 2-bromoacetic acid, forexample t-butyl or methyl bromoacetate, in the presence of a base suchas potassium carbonate in a polar solvent such as DMF provides alkylatedcompounds 2a. Hydrolysis of the ester either by saponification, in thecase of a methyl or ethyl ester, or by treatment with TFA, in the caseof the t-butyl ester, provides acid 2b which can be reacted with anappropriate amine under various conditions known in the literature forformation of amide bonds to provide compounds of formula 2c. Suitablecoupling reagents for this reaction include carbodiimide reagents,Castro's reagent, 1,1-carbonyldiimidazole, mixed anhydride couplingmethods, etc.

Alternately, the fully elaborated A-B moiety can be prepared as theaniline intermediate, which can then undergo conversion toaminovalerolactams of formula 1d using the methods described above.Thus, the starting 4-iodoaniline is amidated via Ullmann or Buchwaldmethodology as illustrated in Scheme 3 to provide 3a or 3b which can besubsequently converted to the corresponding 3-aminovalerolactams and onto the sulfonamide targets following the steps shown in Schemes 1 and 2above.

Subsequent oxidation of compounds 3a wherein Q′=S e.g. S to SO and SO₂,provides additional intermediates useful in the synthesis of compoundsof this invention.

Alternately, piperidone intermediates 3a (Q′=CH₂) can be prepared viamethod outlined in Scheme 4. BOC-protected 4-iodoaniline is aminatedwith benzophenone imine using the method of Wolfe et al. (Tet. Lett.1997, 38, 6367) to provide the monoprotected 1,4-diaminobenzene 4a.Acylation with 5-bromovalerylchloride followed by cyclization in thepresence of a suitable base, such as potassium t-butoxide, anddeprotection of the BOC protecting group provides aniline 4b.

Similarly, the Ullmann coupling methodology can also be applied toprepare urea analogs 5a as shown in Scheme 5.

Substitution of 5-bromo-2-aminopyridine or 5-bromo-2-aminopyrimidine forthe 4-iodoanilines in the above Schemes provides additionalintermediates 4c and 4d useful in Scheme 1 for the synthesis ofcompounds of the present invention wherein A is a pyridyl or pyrimidinylmoiety.

Compounds of this invention wherein A is a non-aromatic carbocycle canbe prepared from intermediate amine compounds shown in scheme 6 viaprocedures known to those skilled in the art.

Compounds of this invention wherein B is amino acid derivatives can beprepared by following Scheme 7. Thus, 8a can be converted to 8b viaprotection, methylation, and deprotection. Acylation of the analinefollowed by amination of the terminal chloride can provide 8d. Couplingof 8d with the lactam intermediate as described previously can givecompound 8e, which can be transformed to desired compound 8f upondeprotection and sulfonation.

Compounds of this invention wherein B is an 1,1-disubstituted cycloalkylderivative can be prepared as described in Scheme 8. Halogenation of 9acan provide the corresponding 9b, which under Ullmann condition can beconverted to 9c. Reduction of the carboxylic acid group followed byoxidation can give the corresponding aldehyde, which under reductiveamination condition can be transformed to 9d. Deprotection andsulfonation provides the desired compound of this invention 9e.

Alternatively, the pyrrolidinone derivatives can be obtained asdescribed in Scheme 9.

One stereoisomer of a compound of Formula I may display superioractivity compared with the other. Thus, the following stereochemistriesare considered to be a part of the present invention.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Steven D. Young, et al, AntimicrobialAgents and Chemotheraphy, 1995, 2602-2605.

Alternately, single stereoisomers can be obtained by chiral synthesis of(R) or (S)-3-aminovalerolactam 7f from (R) or (S)-ornithine derivative7a as shown in Scheme 10.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 6-Chloronaphthalene-2-sulfonic acid{1-[2-fluoro4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}-amide

Part A. Tetrahydro-furan-2-carboxylic acid (2-fluoro4-iodophenyl)amide:

Tetrahydro-2-furoic acid (4.9 g, 42.19 mmol) was dissolved in CH₂Cl₂(250 mL), and oxalyl chloride (1.5 eq.) was added, followed by dropwiseaddition of DMF (0.5 mL). The resulting mixture was stirred at roomtemperature for 18 h. The solvent was removed in vacuo and the residuedried under vacuum, then dissolved in 250 mL CH₂Cl₂. To this solutionwas added 2-fluoro-4-iodoaniline (10 g, 42.19 mmol) and DMAP (12.9 g,105.48 mmol), and the mixture was stirred at room temperature for 18 h.The solvent was removed and the crude product was purified bychromatography on silica gel (4:1/Hexane:EtOAc) to give the amide (13.4g, 96%) as a solid. MS (API+) m/z 335.9 [(M+H)⁺15], 376.9[(M+H+AcCN)⁺100].

Part B. Acetic acid 1-(2-fluoro-4-iodophenyl)-2-oxo-piperidin-3-ylester:

Boron tribromide (3.78 mmol, 7.8 mL of a 1M solution in CH₂Cl₂) wasadded to a solution of the compound of Ex. 1, Part A (2.53 g, 7.55 mmol) in 40 mL CH₂Cl₂. The mixture was stirred at room temperature for 1.5 hand then evaporated to dryness in vacuo. The crude bromide was dissolvedin heptane (100 mL) and Ac₂O (1.54 g, 15.1 mmol ) was added, after whichthe mixture was heated to reflux for 4 h. The reaction was cooled andconcentrated, then quenched with 200 mL water, and extracted with EtOAc.The combined extracts were washed with H₂O, brine, dried over MgSO₄,filtered and concentrated to give a semi-solid mass (3.7 g). MS (ES⁻)m/z 456.1; 458.1 [(M−H)⁻80]. This product was dissolved in DMA (100 mL),and treated with diisopropylamine (2.3 g, 22.65 mmol), and the resultingmixture was heated to reflux for 18 h. The reaction was cooled to roomtemperature and quenched with 500 mL water, then extracted with EtOAc,washed with brine and dried over MgSO₄. After filtration andconcentration, the crude was purified by chromatography on silica get(4:1/Hexane:EtOAc) to give the the desired acetoxylactam (2.7 g, 96%) MS(ES) m/z 441.0 [(M+Na+AcCN)⁺100].

Part C. 1-(2-Fluoro-4-iodophenyl)-3-hydroxy-piperidin-2-one:

The compound of Ex. 1, Part B (6.1 g, 16.18 mmol) was dissolved in amixture of MeOH:H₂O(50:3 mL)and K₂CO₃ (5.6 g, 40.45 mmol) was added. Theresulting mixture was stirred at room temperature for 18 h. The solventwas removed in vacuo, water was added followed by extraction with EtOAc.The combined extracts were washed with brine, dried over MgSO₄, filteredand concentrated to give (5.3 g, 98%) the alcohol as a white solid. MS(ES) m/z 336.2 [(M+H)⁺100].

Part D.3-(t-Butyldimethylsilanyloxy)-1-(2-fluoro-4-iodophenyl)piperidin-2-one:

A solution of the compound of Ex. 1, Part C (1 g, 2.98 mmol) andimidazole (0.9 g, 13.12 mmol) in 10 mL DMF was treated witht-butyldimethylsilyl chloride (1 g, 6.56 mmol), and the mixture washeated at 40° C. for 18 h. The reaction mixture was cooled to roomtemperature and diluted with 200 mL water, extracted into EtOAc, washedwith water, brine and dried over MgSO₄, followed by filtration andconcentration to give the silyl ether (1.5 g, >99%) MS (API+) m/z 450.1[(M+H)⁺100].

Part E.1-[3-fluoro-4-(3-hydroxy-2-oxopiperidin-1-yl)phenyl]piperidin-2-one:

A mixture of the compound of Ex. 1, Part D, (0.5 g, 1.11 mmol ) ,valerolactam (0.2 g, 2.22 mmol ), K₃PO₄ (0.47 g, 2.22 mmol ),1,2-cyclohexyldiamine (13 mg, 0.11 mmol ), and CuI (2 mg, 0.11 mmol ) in1 mL Dioxane was degassed with N₂ and heated at 85° C. for 18 hr. Thesolvent was removed in vacuo and 50 mL EtOAc was added. The mixture wasfiltered through a pad of Celite, concentrated and purified by prep C18HPLC to give the deprotected product (0.12 g, 26%). MS (ES) m/z 307.3[(M+H)⁺100].

Part F. 1-[4-(3-bromo-2-oxopiperidin-1-yl)-3-fluorophenyl]piperidin-2-one:

The compound of Ex. 1, Part E (0.12 g, 0.39 mmol) was dissolved in 10 mLCH₂Cl₂ and treated with PBr₃ (0.21 g, 0.78 mmol). The mixture wasstirred at room temperature for 18 h then quenched with ice water,extracted into CH₂Cl₂, washed with brine, and dried over MgSO₄. Afterfiltration and concentration, the crude product was purified bychromatography on silica gel (2% MeOH in CH₂Cl₂) to give the bromide (89mg, 62%). MS (ESI) m/z 369.2 [(M+H)⁺90].

Part G. 1-[4-(3-amino-2-oxopiperidin-1-yl)-3-fluorophenyl]piperidin-2-one:

The compound of Ex. 1, Part F (89 mg, 0.24 mmol) was dissolved in 1 LDMF and NaN₃ (47 mg, 0.73 mmol) was added. The resulting mixture washeated at 50° C. for 3 h. Solvent was removed in vacuo and the crudeazide was dried under vacuum. MS(ESI) m/z 332.2 [(M+H)⁺100]. A solutionof the azide in MeOH was added to a suspension of SnCl₂ (68 mg, 0.36mmol) in 2 mL MeOH, and then the mixture was stirred at room temperaturefor 18 h. The solvent was removed in vacuo and 10 mL 1 N NaOH solutionwas added, followed by extracted with CHCl₃. The combined extracts werewashed with brine and dried over MgSO₄. Filtration and concentrationgave the crude amine (83 mg, >90%) as a white solid. MS (ESI) m/z 306.3[(M+H)⁺100].

Part H. 6-Chloronaphthalene-2-sulfonic acid{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amide:

The compound of Ex. 1, Part G in a 1:1 mixture of 1 M potassiumcharbonate solution and ethylacetate was treated with 1.2 eq of6-chloronaphthalene-2-sulfonylchloride, and the resulting mixturestirred for 90 min under N₂. The reaction was then diluted with waterand extracted #X with ethyl acetate. The combined organic layers werewashed with brine and dried over sodium sulfate, filtered and evaporatedin vacuo. Purification by flash chromatography provided the titlecompound . . . ¹H NMR (CD₃OD) δ 8.49 (s, 1H), 8.02 (m, 2H), 7.93 (m,2H), 7.57 (m, 1H), 7.25-7.04 (m, 3H), 4.08 (m, 1H), 3.61 (m, 4H), 2.49(m, 2H), 2.26 (m, 1H), 2.01 (m, 3H), 1.92 (m, 4H). MS (ES) m/z 530.3[(M+H)⁺100].

Part I.{(6-Chloronaphthalene-2-sulfonyl)-[1-(3-fluoro-2-methanesulfonylbiphenyl-4-yl)-2-oxo-piperidin-3-yl]amino}-acetic acid:

A mixture of the compound of Ex. 1, Part H (0.50 g, 0.85 mmole), t-butylbromoacetate (147 ul, 1.0 mmole), 1M potassium carbonate (10 mL) andethyl acetate (10 mL) was stirred under nitrogen for 24 h. The mixturewas diluted with water and extracted with ethyl acetate (3×50 mL),washed with brine, dried over sodium sulfate and concentrated. The crudeester was taken up in methylene chloride and 3 mL of TFA was added. Thismixture was stirred for 2 h at room temperature then concentrated anddried under vacuum to give the desired product. (0.24 g, 44% yield). IH(CDCl₃) δ8.47 (s, 1H), 8.22-8.19 (d, 1H, J=1.5 Hz), 7.91 (s, 4H),7.66-7.55 (m, 3H), 7.34-7.31 (d, 1H, J=1.5 Hz), 7.26-7.21 (m,3H),3.82-3.79 (m, 1H), 3.66-3.52 (m, 2H), 2.71 (s, 3H), 2.63 (m, 1H),2.03-1.98 (m, 2H). MS (ESI+) m/z 645.3 (M+1)⁺.

Part J. 2-{(6-Chioronaphthalene-2-suilfonyl)[-1-(3-fluoro-2-methanesulfonylbiphenyl4-yi)-2-oxo-piperidin-3-yl]-amino}-N-(2-dimethylaminoethyl)-N-methylacetamide,trifluoroacetate:

A solution of the compound of Ex. 1, Part H (25 mg, 0.004mmole),N,N,N′-trimethylethylenediamine (6.0 mg, 0.006 mmole), and4-methylmorpholine (11 ul) and DMF(1 mL) was treated with Castro'sReagent (26 mg, 0.006 mmole), and the resulting mixture was stirredunder nitrogen for an additional 48 h. The crude mixture was evaporatedin vacuo and purified by prep LC/MS to provide the title compound (18mg, 64%). ¹H (75%CD₃OD:25%C₆D₆) δ 8.58 (s, 1H), 8.14-8.12 (d, 1H,J=5.78Hz.), 7.99-7.98 (d, 1H, J=11.5 Hz), 7.92-7.90(d,1H, J=11.5Hz),7.86-7.85 (m, 2H), 7.58-7.55 (m, 1H), 7.52-7.48 (m, 2H), 7.20-7.15(m,3H), 4.77-4.76 (m, 1H), 4.23-4.11 (dd, 2H, J=20.2, J=37.1), 3.69-3.61(m, 2H), 3.47-3.42 (m, 1H), 3.37-3.35 (m, 1H), 3.30-3.12 (m, 2H), 3.05(s, 1H), 2.79(s,9H), 2.27-2.25(m, 1H), 2.14 (bs, 1H), 1.91-1.75(m, 2H).MS (ESI+) 729.0 (M+1)⁺.

Example 2 6-Chloronaphthalene-2-sulfonic acid{1-[2-fluoro4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amide

Part A:1-[3-Fluoro4-(3-hydroxy-2-oxo-piperidin-1-yl)phenyl]-1H-pyridin-2-one:

A mixture of the compound of Ex. 1, Part C (1 g, 2.98 mmole),2-hydroxypyridine (1.4 g, 14.93 mmole), K₂CO₃ (4.1 g, 29.85 mmole) andCul (0.28 g, 1.49 mmole) in DMSO (15 mL) was degassed and then heated at140° C. for 3 h. The reaction was cooled to room temperature and 50 mLof saturated NH₄Cl soln. was added. Mixture was extracted with methylenechloride and the combined organic extracts were washed with water andbrine then dried over anh. MgSO₄, filtered and concentrated in vacuo.Crude extract was purified by silica gel chromatography (5% MeOH inCH₂Cl₂) to provide the product (0.5 g, 56%). MS m/z 303.2 (M+-H)⁺. ¹HNMR (CDCl₃)δ 7.45-7.22 (m, 5H), 6.69 (m, 1H), 6.29 (m, 1H), 4.26 (m,1H), 3.64 (m, 2H), 2.45 (m, 1H), 2.13 (m, 2H), 1.94 (m, 1H).

Part B.1-[4-(3-amino-2-oxo-piperidin-1-yl)-3-fluorophenyl]-1H-pyridin-2-one:

Phosphorus tribromide (0.9 g, 3.3 mmole) was added to a solution of thecompound of Ex. 2, Part A (0.5 g, 1.65 mmole) in 20 mL methylenechloride and the mixture was stirred overnight at room temperature.Reaction was quenched by addition of water and layers separated. Aqueouswas reextracted with CH₂Cl₂ and combined extracts washed with brine,dried over MgSO₄, filtered and concentrated in vacuo to give the bromide(0.46 g, 77%) which was used without purification. The bromide wasdissolved in DMF (5 mL) and treated with sodium azide (0.33 g, 5.05mmole). The mixture was heated in a 50° C. oil bath for 3 h. Reactionwas cooled to room temperature, poured into water and extracted intoEtOAc. Purification on silica gel (2% MeOH in CH₂Cl₂) provided the azide(0.31 g, 76%). A mixture of the azide and SnCl₂ (0.27 g, 1.42 mmole) inmethanol (10 mL) was stirred at room temperature overnight. Solvent wasremoved in vacuo and 30 mL 1N NaOH was added to the residue followed byextraction with chloroform. Extracts were combined, washed with brine,dried and concentrated to dryness in vacuo to provide the amine (0.24 g,86%). ¹H NMR (CDCl₃)δ 7.41 (m, 2H), 7.37 (m, 2H), 7.24 (m, 1H), 6.67 (m,1H), 6.27 (m, 1H), 3.67 (m, 3H), 2.35 (m, 1H), 2.05 (m, 2H), 1.95 (m,1H). MS m/z 302.3 (M+H)⁺.

Part C. 6-Chloronaphthalene-2-sulfonic acid[1-(2-fluoro4-pyridin4-yl-phenyl)-2-oxo-piperidin-3-yl]lamide:

This compound was prepared from the compound of Ex. 2, Part B and6-chloronaphthylsulfonyl chloride following the procedure described forEx. 1, Part H to provide the title compound in 76% yield after prep C18HPLC. ¹H NMR (CD_(3 OD) δ)8.50 (s, 1H), 8.00 (m, 2H), 7.94 (s, 2H), 7.57(m, 3H), 7.38 (m, 2H), 7.20 (m, 1H), 6.59 (m, 1H), 6.45 (m, 1H), 4.15(m, 1H), 3.60 (m, 2H), 2.25 (m, 1H), 2.01 (m, 3H). MS (ESI+) m/z 526.3[(M+H)⁺100].

Example 3 6-Chlorothieno [2,3-b]pyridine-2-sulfonic acid{1-[2-fluoro4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxopiperidin-3-yl}amide

A mixture of the compound of Ex. 2, Part B (50 mg, 0.17 mmole),6-chlorothieno[2,3-b]pyridine-2-sulfonylchloride (prepared as describedin WO9937304, 53 mg, 0.199 mmole), 2mL chloroform and 1 mL of a 1Msolution of K₂CO₃ was stirred at room temperature overnight. Additionalchloroform was added and the phases were separated. Organic layer waswashed with brine and dried over MgSO₄, filtered and evaporated. PrepHPLC (C18) of the residue provided the title compound (60 mg, 68%). ¹HNMR (CD₃CN) δ 8.27 (m, 1H), 7.93 (s, 1H), 7.49 (m, 2H), 7.37 (m, 2H),7.23 (m, 2H), 6.49 (m, 2H), 6.27 (m, 1H), 4.13 (m, 1H), 3.61 (m, 2H),2.35 (m, 2H), 2.04 (m, 2H). MS (ES) m/z 533.2 [(M+H)⁺100].

Example 4 6-Chloronaphthalene-2-sulfonic acid{1-[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenyl]-2-oxo-piperidin-3-yl}-amide

Part A.1-[4-(2-Dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenyl]-3-hydroxy-piperidin-2-one:

A mixture of the compound of Ex. 1, Part C (0.5 g, 1.49 mmole),2-dimethylaminomethylimidazole (0.22 g, 1.79 mmole), K₂CO₃ (0.6 g, 4.5mmole) and CuI (0.1 g, 0.746 mmole) in DMSO (10 mL) was degassed andthen heated at 140° C. for 3 h. Cooled to room temperature and dilutedwith saturated NH₄Cl solution. Product was extracted into chloroform(3×), washed with brine, dried and evaporated. Flash chromatography onsilica gel (2% MeOH in CH₂Cl₂) provided the product (0.35 g, 71%). ¹HNMR (CDCl₃)δ 7.70 (m, 1H), 7.39 (m, 2H), 7.11 (m, 2H), 4.25 (m, 1H),3.70 (m, 3H), 3.40 (2, 2H), 2.45 (m, 1H), 2.28 (s, 6H), 2.10 (m, 2H),1.95 (m, 1H). MS m/z 333.3 (M+H)⁺.

Part B.3-amino-1-[4-(2-Dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenyl]piperidin-2-one:

The compound of Ex. 4, Part A was converted in three steps into thecorresponding amino compound as described in Part B of Ex. 2 above. MSm/z 332.3 (M+H)⁺.

Part C. 6-Chloronaphthalene-2-sulfonic acid{1-[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenyl-2-oxo-piperidin-3-yl-amide:

The title compound was prepared in 70% yield from the amine in Part Babove and 6-chloronaphthylsulfonyl chloride following the proceduredescribed for Ex. 1, Part H. ¹H NMR (CD₃OD) δ 8.49 (x, 1H), 8.03 (m,2H), 7.95 (s, 2H), 7.58 (m, 1H), 7.40 (m, 3H), 7.22 (m, 2H), 4.36 (s,2H), 4.15 (m, 1H), 3.60 (m, 2H), 2.82 (s, 6H), 2.25 (m, 1H), 2.06 (m,3H). MS (ES) m/z 556.4 [(M+H)⁺100].

Similarly prepared from the compound of Ex. 4, Part B and the indicatedsulfonyl chlorides were the following compounds in Table 2. TABLE 2

Ex. No. RSO₂Cl R (M + H)+ 5 6-chlorothieno[2,3- b]pyridine-2-sulfonylchloride

563.2 6 5-chlorothieno[3,2- b]pyridine-2- sulfonylchloride

563.2 7 5-chlorobenzothienyl- 2-sulfonylchloride

562.2

Example 8 6-Chlorothieno[2,3-b]pyridine-2-sulfonic acid{1-[4-(2-methylaminomethylimidazol-1-yl)-2-fluoro-phenyl]-2-oxo-piperidin-3-yl}amide,trifluoroacetate salt

Part A.1-[2-Fluoro-4-(2-methylaminomethylimidazol-1-yl)-phenyl]-3-hydroxy-piperidin-2-one,trifluoroacetate salt:

This compound was prepared according to the procedure of Ex. 4, Part Afrom the compound of Ex. 1, Part C and 2-(methylaminomethyl)imidazoleand isolated as its TFA salt in 44% yield after C18 HPLC. ¹H NMR δ 7.57(m, 1H), 7.42 (m, 2H), 7.34 (m, 1H), 7.19 (s, 1H), 4.31 (s, 2H), 4.25(m, 1H), 3.72 (m, 1H), 3.62 (m, 1H), 2.75 (s, 3H), 2.25 (m, 1H), 2.12(m, 2H), 1.95 (m, 1H). MS m/z 319.3 (M+H)⁺.

Part B.1{1-[3-Fluoro-4-(3-hydroxy-2-oxo-piperidin-1-yl)-phenyl]-1H-imidazol-2-ylmethyl}methylcarbamicacid t-butyl ester:

A mixture of the compound of Ex. 18, Part A (0.22 g, 0.51 mmol) andNaHCO₃ (0.13 g, 1.53 mmol) in 10 mL MeOH was treated with Boc₂O (0.17 g,0.76 mmol), and the resulting mixture was stirred at room temperaturefor 18 h. the solvent was removed in vacuo and 50 mL water was added,followed by extraction into CHCl₃. The combined extracts were washedwith brine, dried over MgSO₄, filtered and concentrated to give the BOCprotected product (0.19 g, 90%) as a white solid. MS (ES) m/z 419.3[(M+H)⁺90]; m/z 363.3 [(M+H−tBu)⁺100].

Part C. Methanesulfonic acid1-(4-{2-[(t-butoxycarbonyl-methylamino)-methyl]-imidazol-1-yl}-2-fluoro-phenyl)-2-oxo-piperidin-3-ylester:

To a solution of the compound of Ex. 8, Part B (0.19 g, 0.45 mmol ) in 5mL CH₂Cl₂ cooled to 0° C., was added Et₃N (69 mg, 0.68 mmol ), followedby dropwise addition of methanesulfonyl chloride (57 mg, 0.5 mmol).After addition, the reaction mixture was stirred at 0° C. and slowlyallowed to assume room temperature. Stirring at RT was continued for 7h. Solvent was removed in vacuo and the residue dried under vacuum. Usedcrude in next step. MS (ES) m/z 497.3 [(M+H)⁺100].

Part D.{1-[4-(3-Azido-2-oxo-piperidin-1-yl)-3-fluoro-phenyl]-1H-imidazol-2-ylmethyl}-methyl-carbamicacid t-butyl ester:

The product from Part C above was dissovled in 2 mL DMF, and NaN₃ (0.1g, 1.61 mmol) was added. The mixture was stirred at room temperature for18 h. Reaction was diluted with water, extracted with CHCl₃, the organiclayer was washed with water and brine, then dried over MgSO₄, filteredand concentrated to give the azide (0.18, >90% over two steps). MS (ES)m/z 444.3 [(M+H)⁺100].

Part E.{1-[4-(3-Amino-2-oxo-piperidin-1-yl)-3-fluoro-phenyl]-1H-imidazol-2-ylmethyl}-methylcarbamicacid t-butyl ester:

The compound of Ex. 8, Part D (0.18 g, 0.41 mmole) was dissolved in 5 mLMeOH and 20 mg of 5% Pd/C was added. The mixture was kept under 50 psiof H₂ on a Parr shaker for 18 h. Catalyst was removed by filtrationthrough a pad of Celite and filtrate concentrated in vacuo to give theamine (0.11 g, 66%) which was used crude in the next step. MS (ES) m/z418.3 [(M+H)⁺90].

Part F.(1-{4-[3-(6-Chlorothieno[2,3-b]pyridine-2-sulfonylamino)-2-oxo-piperidin-1-yl]-3-fluorophenyl}-1H-imidazol-2-ylmethyl)-methylcarbamicacid t-butyl ester:

A mixture of the compound of Ex. 8, Part E (0.11 g, 0.264 mmole),6-chlorothieno[2,3-b]pyridine-2-sulfonylchloride (85 mg, 0.316 mmole)and Et₃N (0.11 mL, 0.79 mmole) in 2 mL CH₂Cl₂ was stirred at roomtemperature for 2 h. Water was then added and the phases separated.Aqueous layer was reextracted with CH₂Cl₂ (3×) and combined extractswashed with brine and dried over MgSO₄, filtered and concentrated invacuo to provide the product (45 mg, 26%). MS 649.3 (M+H)⁺.

Part G. 6-Chlorothieno[2,3-b]pyridine-2-sulfonic acid{1-[4-(2-methylaminomethylimidazol-1-yl)-2-fluorophenyl]-2-oxo-piperidin-3-yl}amide,trifluoroacetate salt:

The compound of Ex. 8, Part F (21 mg, 0.032 mmole) was dissolved in 1 mLCH₂Cl₂ and treated with 2 mL TFA. This mixture was stirred at roomtemperature for 3 h, then stripped to dryness and purified by prep LC/MSto provide the title compound as its TFA salt (3.2 mg). ¹H NMR (CD₃OD) δ8.26 (m, 1H), 7.91 (s, 1H), 7.47 (m, 2H), 7.35 (m, 2H), 7.26 (m, 1H),7.14 (m, 1H), 4.25 (m, 1H), 4.26 (s, 2H), 3.60 (m, 2H), 2.69 (s, 3H),2.30 (m, 1H), 2.08 (m, 3H). MS (ES) m/z 549.2 [(M+H)⁺100].

Example 9((6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-methylaminomethylimidazol-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)aceticacid methyl ester

Part A.[[1-(4-{2-[(t-Butoxycarbonylmethylamino)-methyl]-imidazol-1-yl}-2-fluorophenyl)-2-oxo-piperidin-3-yl]-(6-chlorothieno[2,3-b]pyridine-2-sulfonyl)amino]aceticacid methyl ester:

A mixture of the compound of Ex. 8, Part F (20 mg, 0.031 mmole), methylbromoacetate (7.1 mg, 0.046 mmole) and K₂CO₃ (5.1 mg, 0.04 mmole) in 1mL DMF was stirred at room temperature overnight. Water was added andmix extracted with chloroform. Organic phase was dried and concentrated.Used crude in next step. MS m/z 721.4 (M+H)⁺.

Part B.((6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-methylaminomethylimidazol-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)aceticacid methyl ester:

The compound of Part A above was deprotected as described for Ex. 8,Part G to give the title compound after prep LC/MS. ¹H NMR (CD3OD) δ8.28 (m, 1H), 7.96 (s, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 7.25 (m, 1H),7.14 (m, 1H), 4.80 (m, 1H), 4.21 (s, 2H), 4.19 (m, 1H), 3.80 (m, 1H),3.72 (s, 3H), 3.70 (m, 1H), 3.55 (m, 1H), 2.68 (s, 3H), 2.40 (m, 1H),2.19 (m, 3H).

Example 102-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide

Part A.((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}-amino)aceticacid t-butyl ester:

The compound of Ex. 2 (37.7 mg, 0.07 mmole) was dissolved in 1 mL of DMFand treated with t-butyl bromoacetate (0.016 mL, 0.108 mmole) and K₂CO₃(12 mg, 0.087 mmole). The whole was stirred at room temperatureovernight. Reaction was diluted with water and extracted with CHCl₃.Extracts were combined, washed with brine, dried and evaporated.

Part B.((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}-amino)aceticacid:

Crude product from Part A was dissolved in a mixture of 1 mL CH₂Cl₂ and2 mL TFA and stirred at room temp. for 6 h. Stripped to dryness.

Part C.2-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide:

A mixture of crude acid from Part B (39 mg, 0.067 mmole),N,N,N′-trimethylethylenediamine (0.009 mL, 0.07 mmole), triethylamine(0.028 mL, 0.2 mmole) and DMAP (8.1 mg, 0.067 mmole) in 1 mL DMF wastreated with Castro's reagent (59.1 mg, 0.134 mmole) and the mixturestirred and heated in 50° C. oil bath overnight. Stripped to dryness andpurified by prep LC/MS to provide the title compound as a TFA salt (17.2mg, 33%). ¹H NMR (CD3OD) δ 8.56 (s, 1H), 8.03 (m, 2H), 7.97 (s, 2H),7.61 (m, 3H), 7.57 (m, 1H), 7.36 (m, 1H), 7.24 (m, 1H), 6.61 (m, 1H),6.45 (m, 1H), 4.78 (m, 1H), 4.22 (m, 2H), 3.75 (m, 2H), 3.53 (m, 2H),3.24 (m, 2H), 3.17 (s, 3H), 2.85 (s, 3H), 2.77 (s, 3H), 2.25 (m, 1H),2.10 (M, 3H). MS (ES) m/z 668.2 [(M+H)⁺100].

Examples 11 and 12(+)-2-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide(Example 11) and(−)-2-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide(Example 12)

The compound of Ex 10 was separated by chiral HPLC (Column: AD,MeOH:iPrOH:hexane 1:1:1) to provide the two enantiomers. Peak 1 (Ex.11): [α]_(D)+20.0° (MeOH). ¹H NMR (CD3OD) δ 8.55 (s, 1H), 8.01 (m, 2H),7.96 (m, 2H), 7.59 (m, 3H), 7.46 (m, 1H), 4.26 (m, 1H), 4.15 (m, 1H),3.67 (m, 2H), 3.59 (m, 2H), 3.13 (s, 3H), 3.03 (m, 2H), 2.65 (s, 6H),2.25 (m, 1H), 2.05 (m, 3H). MS (ES) m/z 668.4 [(M+H)⁺100].

Peak 2 (Ex. 12): [α]_(D)−18.2° (MeOH). ¹H NMR (CD3OD) δ 8.52 (s, 1H),8.03 (m, 1H), 7.93 (m, 2H), 7.56 (m, 3H), 7.45 (m, 1H), 7.33 (m, 1H),7.22 (m, 1H), 6.58 (m, 1H), 6.43 (m, 1H), 4.70 (m, 1H), 4.29 (m, 1H),4.10 (m, 1H), 3.65 (m, 1H), 3.54 (m, 3H), 3.07 (s, 3H), 2.80 (m, 2H),2.47 (s, 6H), 2.25 (m, 1H), 2.05 (m, 3H). MS (ES) m/z 668.4 [(M+H)⁺100].

Example 132-((6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}-amino)-N-methyl-acetamide

Part A.((6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}-amino)-aceticacid t-butyl ester:

The compound of Ex. 3 was treated with t-butyl bromoacetate in thepresence of K₂CO₃ using the procedure described for Ex. 10, Part A toprovide the desired product in 91% yield. ¹H NMR (CDCl₃) δ 8.06 (m, 1H),7.87 (s, 1H), 7.34 (m, 4H), 7.24 (m, 2), 6.68 (m, 1H), 6.26 (m, 1H),4.70 (m, 1H), 4.14 (d, J=18.3 Hz, 1H), 3.65 (d, J=18.3 Hz, 1H), 3.60 (m,1H), 2.60 (m, 1H), 2.17 (m, 3H), 1.50 (2, 9H). MS m/z 647.3 [(M+H)⁺,45%], 591.2 [(M+H−tBu)⁺, 100%].

Part B.((6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}-amino)-aceticacid:

Deprotection of the t-butyl ester was carried out with TFA in CH₂Cl₂ aspreviously described to give the acid which was used withoutpurification in the next step.

Part C.2-((6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}amino)-N-methylacetamide:

A mixture of the acid from Part B (30 mg, 0.051 mmole), methylaminehydrochloride (1.73 mg, 0.056 mmole), triethylamine (0.021 mL, 0.153mmole), and DMAP (6.2 mg, 0.051 mmole) in DMF (1 mL) was treated withCastro's reagent (45 mg, 0.102 mmole) and the whole was stirred at 50°C. for 6 h. Reaction was worked up as described above and productpurified by prep LC/MS to provide the title compound. ¹H NMR (CD₃OD) δ8.33 (m, 1H), 8.01 (s, 1H), 7.62 (m, 2H), 7.53 (m, 2H), 7.30 (m, 1H),7.29 (m, 1H), 6.62 (m, 1H), 6.47 (m, 1H), 4.70 (m, 1H), 4.08 (m, 1H),3.75 (m, 2H), 3.60 (m, 1H), 2.64 (m, 3H), 2.38 (m, 2H), 2.15 (m, 2H). MS(ES) m/z 604.2 [(M+H)⁺100].

Example 142-((6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxo-piperidin-3-yl}-amino)-N-(2-dimethylaminoethyl)-N-methylacetamide

The compound of Ex. 13, Part B was coupled with N,N,N′-trimethylethylenediamine according to the procedure described for Ex. 8, Part C toprovide the title compound after prep LC/MS. ¹H NMR (CD₃OD) δ 8.33 (m,1H), 8.07 (s, 1H), 7.61 (m, 2H), 7.52 (m, 2H), 7.34 (m, 1H), 7.29 (m,1H), 6.62 (m, 1H), 6.47 (m, 1H), 4.85 (m, 2H), 4.25 (m, 1H), 4.13 (m,1H), 3.90 (m, 1H), 3.75 (m, 1H), 3.60 (m, 2H), 3.17 (s, 3H), 2.92 (s,3H), 2.85 (s, 3H), 2.65 (m, 1H), 2.35 (m, 2H), 2.15 (m. 2H). MS (ES) m/z675.3 [(M+H)⁺100].

Example 15 6-Chloronaphthalene-2-sulfonic acid{1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}-amide

Part A. 1-[4-(3-hydroxy-2-oxo-piperidin-1-yl)-phenyl]-1H-pyridin-2-one:

A mixture of 1-(4-bromophenyl)-3-hydroxy-piperidin-2-one (2 g, 7.43mmole), 2-hydroxypyridine (3.5 g, 37.17 mmole), K₂CO₃ (10.3 g, 74.35mmole) and 1,10-phenanthroline (0.67 g, 3.71 mmole) in DMSO (25 mL) wasdegassed and then CuI (0.7 g, 3.71 mmole) was added. The wholes washeated in a 140° C. oil bath with stirring under N₂ for 6 h. Cooled toroom temperature and worked up as previously described. Purification byprep HPLC provided the product (0.58 g, 28%). MS m/z 285.2 (M+H)⁺.

Part B. 1-[4-(3-amino-2-oxo-piperidin-1-yl)-phenyl]-1H-pyridin-2-one:

The compound of Part A was converted to the corresponding mesylate,followed by displacement with sodium azide and reduction with tinchloride using the procedures of Ex. 17, Part C and Ex. 10, Part Drespectively to provide the amine in 65% yield over the three steps. ¹HNMR (CDCl₃) δ 7.40 (m, 6H), 6.67 (m, 1H), 6.26 (m, 1H), 3.70 (m, 2H),3.55 (m, 1H), 2.35 (m, 1H), 1.75 (m, 1H). MS m/z 284.1 (M+H)⁺.

Part C. 6-Chloronaphthalene-2-sulfonicacid{1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}-amide:

The amine was reacted with 6-chloronaphthylsulfonyl chloride accordingto the procedure of Ex. 1, Part H to provide the title compound afterprep LC/MS. ¹H NMR (CDCl₃) δ 8.50 (s, 1H), 8.01 (m, 2H), 7.98 (m, 2H),7.56 (m, 3H), 7.34 (m, 4H), 6.60 (m, 1H), 6.45 (m, 1H), 4.10 (m, 1H),3.65 (m, 2H), 2.25 (m, 1H), 2.00 (m, 3H). MS (ES) m/z 507.9 [(M+H)⁺100].

Example 16 6-Chlorothieno[2,3-b]pyridine-2-sulfonic acid{1-[4-(2-oxo-2H-pyridin-1-yl)phenyl]-2-oxopiperidin-3-yl}amide

The title compound was prepared from the compound of Ex. 15, Part B bytreatment with 6-chlorothieno[2,3-b]pyridine-2-sulfonylchloride by themethod described in Ex. 3. ¹H NMR (CDCl₃) δ 8.30 (m, 1H), 0.97 (s, 1H),7.58 (m, 2H), 7.78 (m, 1H), 7.38 (m, 4H), 6.60 (m, 1H), 6.45 (m, 1H),4.20 (m, 1H), 3.70 (m, 2H), 2.30 (m, 1H), 2.05 (m, 3H). MS m/z 514.8(M+H)⁺.

Example 172-((6-Chloronaphthalene-2-sulfonyl)-{1-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-2-oxo-piperidin-3-yl}amino)-N-(2-dimethylaminoethyl)-N-methylacetamide

The title compound was prepared from the compound of Ex. 1 following theprocedures outlined for the preparation of Ex. 10. ¹H NMR (CD₃OD) δ 8.59(s, 1H), 8.05 (m, 2H), 7.95 (s, 2H), 7.30 (m, 1H), 7.15 (m, 2H), 4.75(m, 1H), 4.19 (s, 2H), 3.80-3.40 (m, 6H), 3.25 (m, 2H), 3.17 (s, 3H),2.81 (s, 3H), 2.71 (s, 3H), 2.45 (m, 2H), 2.10 (m, 1H), 2.05 (m, 3H),1.93 (m, 4H). MS m/z 672.4 (M+H)⁺.

Example 18N-{4-[3-(6-Chloro-naphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-2-dimethylamino-N-methyl-acetamide

Part A:

To a solution of 4-iodoaniline (10.0 g, 45.6 mmol) in dichloromethane(100 mL) were slowly added pyridine (7.4 mL, 91.3 mmol) and TFAA (7.1mL, 50.22 mmol) at 0° C. The reaction was stirred at 0° C. for one hour.Water (50 mL) was added, and the organic layer was separated. Theaqueous layer was further extracted with dichloromethane. The organiclayers were combined, washed with water and brine, dried over magnesiumsulfate, and filtered. Removal of the solvent gave the desired2,2,2-trifluoro-N-(4-iodo-phenyl)-acetamide as a white solid.

Part B:

The above-obtained amide was dissolved in acetone (80 mL), to whichpotassium carbonate (15.75 g, 114.1 mmol) and iodomethane (9.6 mL, 114.1mmol) were added. The reaction was heated to reflux for 2 hours andcooled, and the resulting solid was filtered. The solvent was removedfrom the filtrate. The residue was dissolved in dichloromethane, washedwith water and brine, and dried over sodium sulfate. After filtrationand removal of solvent, the solid was further dried in vacuo to give thedesired 2,2,2-trifluoro-N-(4-iodo-phenyl)-N-methyl-acetamide as a whitesolid. MS found: (M+1)⁺=330.05.

Part C:

The product obtained above was dissolved in methanol/water (2:1, 100 mL)and potassium carbonate (15.75 g, 114.1 mmol) was added. The mixture wasstirred at rt for 6 hours. Dichloromethane (100 mL) was added, and theorganic layer was separated, washed with water and brine, and dried overmagnesium. Removal of the solvent gave the desired(4-iodo-phenyl)-methyl-amine as a dark colored, low-melting solid. MSfound: (M+1)⁺=234.11.

Part D:

The product obtained above was dissolved in dichloromethane (100 mL), towhich DIEA (12 mL) and chloroacetyl chloride (12 mL) were slowly addedat 0° C. The reaction was stirred from 0° C. to rt for 4 hours, washedwith 1.0 N HCl (2×) and brine, and dried over magnesium sulfate. Aftersolvent removal, the crude product was purified by chromatography usingethyl acetate/hexane as eluent (2:8 to 4:6 ethyl acetate:hexane) to givethe desired 2-chloro-N-(4-iodo-phenyl)-N-methyl-acetamide as a brownsolid. MS found: (M+1)⁺=310.23.

Part E:

The product from part D (1.54 g, 4.98 mmol) was dissolved in THF/water(20/5 mL) and potassium carbonate (1.00 g, 7.25 mmol) followed bydimethyl amine (2.0M in THF, 4.0 mL, 8.0 mmol) were added at rt. Themixture was stirred at rt over night. Most of the solvent was removedunder reduced pressure. Dichloromethane was added to the residue. Thesolution was washed with saturated sodium bicarbonate and brine anddried over sodium sulfate, and the solvent was removed. The residue wasfurther dried in vacuo to give the desired2-dimethylamino-N-(4-iodo-phenyl)-N-methyl-acetamide as a light brownsolid. MS found: (M+1)⁺=319.11.

Part F:

An oven-dried flask was charged with the product from part D (450 mg,1.42 mmol), (2-oxo-piperidin-3-yl)-carbamic acid benzyl ester (333 mg,1.34 mmol), CuI (27 mg, 0.14 mmol), and potassium phosphate (750 mg,3.54 mmol). The flask was degassed and refilled with nitrogen. To themixture was added anhydrous dioxane (10 mL) andtrans-1,2-cyclohexanediamine (20 mg). The reaction was stirred at refluxunder nitrogen for 10 hours and cooled, and the resulting solid filteredoff. The filtrate was purified with HPLC using acetonitrile/water (5:95to 95:5 gradient) as eluent to give the desired(1-{4-[(2-dimethylamino-acetyl)-methyl-amino]-phenyl}-2-oxo-piperidin-3-yl)-carbamicacid benzyl ester. MS found: (M+1)⁺=439.27.

Part G:

The above-obtained product (60 mg) was dissolved in acetonitrile (5.0mL) and cooled to 0° C., to which iodotrimethylsilane (0.3 mL) wasadded. The reaction was stirred from 0° C. to rt for 4 hours. Thesolvent was removed under reduced pressure, and the desired productN-[4-(3-amino-2-oxo-piperidin-1-yl)-phenyl]-2-dimethylamino-N-methyl-acetamidewas separated by HPLC using acetonitrile/water as eluent (5% to 95%gradient). MS found: (M+1)⁺=305.24.

Part H:

The amine from part G (50 mg) was dissolved in dichloromethane (3.0 mL)and 6-chloronaphthene-2-sulfonyl chloride (30 mg) and TEA (0.1 mL) wereadded. The reaction was stirred at rt for 4 hours. The solvent wasremoved under reduced pressure, and the residue was purified by HPLCusing acetonitrile/water (30% to 95% gradient) as eluent to give thetitle compound as a white solid. MS found: (M+1)⁺=529.16/531.17.

Example 19{[(4-{3-[(6-Chloro-naphthalene-2-sulfonyl)-methoxycarbonylmethyl-amino]-2-oxo-piperidin-1-yl}-phenyl)-methyl-carbamoyl]-methyl}-methoxycarbonylmethyl-dimethyl-ammonium

Following a procedure analogous to that described in Example 18, thetitle compound was obtained. MS found: (M+1)⁺=673.3.

Example 20N-{4-[3-(6-Chloro-naphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-N-methyl-2-pyrrolidin-1-yl-acetamide

Following a procedure analogous to that described in Example 18, thetitle compound was obtained. MS found: (M+1)⁺=555.2.

Example 21N-{4-[3-(6-Chloro-naphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-2-dimethylamino-N-methylacetamide

Following a procedure analogous to that described in Example 18, thetitle compound was obtained. MS found: (M+1)⁺=529.2.

Example 22N-{4-[3-(6-Chloro-thieno[2,3-b]pyridine-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-2-dimethylamino-N-methyl-acetamide

Following a procedure analogous to that described in Example 18, thetitle compound was obtained. MS found: (M+1)⁺=529.2.

Example 23((5-Chloro-thieno[3,2-b]pyridine-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-aceticacid methyl ester

Following a procedure analogous to that described in Example 2, thetitle compound was obtained. MS found: (M+1)⁺=587.1.

Example 24 6-Chloro-naphthalene-2-sulfonic acidmethyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=522.1.

Example 25 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic acidmethyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=529.1.

Example 26 6-Chloro-naphthalene-2-sulfonic acidethyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=536.2.

Example 27 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic acidethyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=543.1.

Example 282-((6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=587.16.

Example 29 6-Chloro-naphthalene-2-sulfonic acidcyanomethyl-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=605.2.

Example 30 6-Chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-thiazol-4-ylmethyl-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=547.2.

Example 31 6-Chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-pyridin-3-ylmethyl-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=599.3.

Example 32 6-Chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-pyridin-2-ylmethyl-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=599.3.

Example 33 6-Chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-pyridin-4-ylmethyl-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=599.3.

Example 342-((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-N-methyl-acetamide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=579.2.

Example 352-((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=565.1.

Example 36 6-Chloro-naphthalene-2-sulfonic acid(2-methyl-thiazol-4-ylmethyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=619.1.

Example 374-Methoxy-N-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-benzenesulfonamide

Following a procedure analogous to that described in Example 2, thetitle compound was obtained. MS found: (M+1)⁺=454.3.

Example 38 5-Chloro-thiophene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Example 2, thetitle compound was obtained. MS found: (M+1)⁺=464.1.

Example 39((5′-Chloro-[2,2′]bithiophenyl-5-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-aceticacid methyl ester

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=618.1.

Example 403-Chloro-N-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-benzenesulfonamide

Following a procedure analogous to that described in Example 2, thetitle compound was obtained. MS found: (M+1)⁺=458.2.

Example 41((4-Methoxy-benzenesulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-aceticacid methyl ester

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=526.2.

Example 42((5-Chloro-thiophene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-aceticacid methyl ester

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=536.1.

Example 432-((4-Methoxy-benzenesulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=511.2.

Example 44((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-aceticacid tert-butyl ester

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+Na)⁺=644.1.

Example 452-((5-Chloro-thiophene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=521.1.

Example 46((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-aceticacid

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=566.1.

Example 47 5-Chloro-thieno[3,2-b]pyridine-2-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Example 2, thetitle compound was obtained. MS found: (M+1)⁺=515.3.

Example 48 5′-Chloro-[2,2′]bithiophenyl-5-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Example 2, thetitle compound was obtained. MS found: (M+1)⁺=546.2.

Example 492-((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-N-(2-hydroxy-ethyl)-acetamide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=609.3.

Example 50N-Carbamoylmethyl-2-((6-chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-acetamide

Following a procedure analogous to that described in Examples 2 and 13,the title compound was obtained. MS found: (M+1)⁺=622.3.

Example 51 6-Chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-pyrrolidin-3-yl}-amide

Following a procedure analogous to that described in Example 2, thetitle compound was obtained. MS found: (M+1)⁺=498.2.

Example 52 6-Chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-pyrrolidin-3-yl}-amide

Following a procedure analogous to that described in Example 2, thetitle compound was obtained. MS found: (M+1)⁺=494.1.

Example 53 6-Chloro-thieno[2,3-b]pyridine-2-sulfonicacid{2-oxo-1-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-piperidin-3-yl}-amide

Part A.

To a mixture of (2-oxo-piperidin-3-yl)-carbamic acid benzyl ester (1.35g, 5.44 mmol) and 1-(4-iodo-phenyl)-cyclopropanecarboxylic acid (1.56 g,5.42 mmol, 1.0 eq) in DMSO (5 mL) was added K₂CO₃ (3.00 g, 21.73 mmol,4.0 eq), CuI (0.52 g, 2.74 mmol, 0.5 eq), and 1,10-phenanthroline (0.50g, 2.74 mmol, 0.5 eq) sequentially. The mixture was heated at 120° C.overnight under N₂. After cooling, EtOAc and H₂O was added. The mixturewas filtered. The filtrate was washed with 1 N NaOH. The aqueous layerwas acidified with conc. HCl, and extracted with EtOAc (3×). Theorganics were washed with brine, dried over MgSO₄, filtered, andconcentrated to give crude1-[4-(3-benzyloxycarbonyl-amino-2-oxo-piperidin-1-yl)-phenyl]-cyclopropanecarboxylicacid (0.69 g, slightly contaminated with disubstituted compound). LC/MS(ESI) 409.2 (M+H).

Part B.

To a solution of the product from Part A (0.69 g, 1.69 mmol) in THF (10mL) at 0° C. under N₂, was added Et₃N (0.42 mL, 3.01 mmol, 1.8 eq),followed by dropwise addition of ClCOOEt (0.23 mL, 2.40 mmol, 1.5 eq).The mixture was stirred at 0° C. for 20 min. It was filtered and rinsedwith THF (2 mL). To the filtrate was added MeOH (2 mL) and NaBH₄ (0.64g, mmol, 5.9 eq) at 0° C. The mixture was stirred at 0° C. for 20 min,sat'd Na₂SO₄ was added. It was partitioned between EtOAc and H₂O. Theorganics were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography(CH₂Cl₂, then CH₂Cl₂:EtOAc=1:1 then EtOAc) to give{1-[4-(1-hydroxymethyl-cyclopropyl)-phenyl]-2-oxo-piperidin-3-yl}-carbamicacid benzyl ester (0.29 g, yield 43.6%). LRMS (ESI) 395.4 (M+H).

Part C.

The product of Part B (0.29 g, 0.74 mmol) and NaOAc (0.16 g, 1.95 mmol,2.6 eq) were stirred in CH₂Cl₂ (5 mL). 4A Molecular sieves (one spatulatip) was added, followed by the addition of PCC (0.27 g, 1.25 mmol, 1.7eq). The mixture was stirred at room temperature for 0.5 h. It wasfiltered through Celite. EtOAc was added and washed with H₂O (2×),brine, dried over MgSO₄, filtered, and concentrated to dryness. Theresidue was stirred in ClCH₂CH₂Cl (2 mL). Pyrolidine (0.2 mL),NaBH(OAc)₃ (0.5 g), and one drop of HOAc were added sequentially. Themixture was stirred at rt for 2h. EtOAc was added. It was washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by FCC (EtOAc, then 5% MeOH in EtOAc) to give{2-Oxo-1-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-piperidin-3-yl}-carbamicacid benzyl ester (96 mg, yield 27%). LRMS (ESI) 478.4 (M+H).

Part D.

The product from Part C (40.0 mg, 0.089 mmol) was dissolved in MeOH (1.5mL), and 10% Pd/C (pipette tip) was added. The reaction vessel waspurged with H₂(g) (3×) and the reaction was allowed to stir for 1.5 h.The mixture was filtered and purified by prep LC/MS to obtained3-amino-1-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-piperidin-2-one(15 mg, yield: 54%). LC/MS (ESI⁺) 314.2 (M+H)⁺, t_(R)=2.18 min (10-90%CH₃CN/H₂O in a 6-min run).

Part E.

To a CH₂Cl₂ (0.5 mL) solution of the product from Part D (7 mg, 0.022mmol) was added 2M Na₂CO₃ (aq) (2 drops) and6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl chloride (11.7 mg, 0.043 mmol,1.95 eq) sequentially. The resulting mixture was stirred at rtovernight. The residue was purified by prep LC/MS to give the titledcompound (2.9 mg, 19%). LC/MS (ESI⁺) 546.7 (M+H)⁺, t_(R)=4.07 min (5-98%CH₃CN/H₂O in a 10-min run). ¹H NMR (CD₃CO, 300 MHz) δ 8.25 (d, J=8 Hz,1H), 7.91 (s, 1H), 7.45 (m, 3H), 7.18 (d, J=8 Hz, 2H), 4.19 (m, 2H),3.61 (m, 2H), 2.95 (m, 4H), 2.15 (m, 4H), 1.85 (m, 2H) 1.30 (m, 2H),1.15 (m, 4H) ppm.

Example 54 6-Chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-piperidin-3-yl}-amide

Following a procedure analogous to that described in Example 53, thetitle compound was obtained. MS found: (M+1)⁺=538.7. ¹H NMR (CD₃CO, 300MHz) δ 8.55 (s, 1H), 8.10 (m, 4H), 7.61 (d, J=8 Hz, 1H), 7.43 (d, J=6Hz, 2H), 7.18 (d, J=6 Hz, 2H), 6.65 (bs, 1H), 3.85 (m, 1H), 3.65 (m,1H), 3.50 (bs, 4H), 2.85 (bs, 6H), 1.83 (bs, 2H), 1.15 (bs, 2H), 0.85(bs, 2H) ppm.

Example 552-((6-Chloro-naphthalene-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-aceticacid methyl ester

The compound of Example 2 was treated with methyl bromoacetate in thepresence of potassium carbonate using the procedure described for thepreparation of compound 9, Part A. Purification by flash chromatographyprovided the title compound. MS(ESI⁺) (M+H)⁺. ¹HNMR (CDCl₃) δ 8.48 (s,1H); 7.85 (m, 4H); 7.53 (m, 2H); 7.37 (m, 3H); 7.27 (m, 2H); 6.85 (m,1H); 6.45 (m, 1H); 4.60 (m, 1H); 4.30 (m, 1H); 3.80 (m, 1H); 3.74 (m,3H); 3.60 (m, 1H); 3.40 (m, 1H); 2.55 (m, 1H); 2.15 (m, 3H) ppm. MS m/z580.0 (M+H)⁺. HRMS calcd for C₂₉H₂₇N₃O₆SCl: 580.1309. Found: 580.1310.

Example 562-((6-Chlorothieno[2,3-b]pyridine-2-sulfonyl)-{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-piperidin-3-yl}-amino)-aceticacid methyl ester

The compound of Example 3 was treated with methyl bromoacetate in thepresence of potassium carbonate using the procedure described for thepreparation of compound 9, Part A. Purification by flash chromatographyprovided the title compound. MS(ESI⁺) (M+H)⁺. ¹HNMR (CDCl₃) δ 8.08 (m,1H); 7.89 (s, 1H); 7.48 (m, 1H); 7.39 (m, 2H); 7.31 (m, 4H); 6.78 (m,1H); 6.36 (m, 1H); 4.72 (m, 1H); 4.27 (m, aH); 3.83 (m, 1H); 3.78 (s,3H); 3.74 (m, 1H); 3.66 (m, 1H); 2.60 (m, 1H); 2.16 (m, 3H). MS m/z586.9 (M+H)⁺. HRMS calcd for C₂₆H₂₄N₄O₆S₂Cl: 587.0826. Found: 587.0813.

Utility

The compounds of this invention are inhibitors of factor Xa and areuseful as anticoagulants for the treatment or prevention ofthromboembolic disorders in mammals (i.e., factor Xa-associateddisorders). In general, a thromboembolic disorder is a circulatorydisease caused by blood clots (i.e., diseases involving fibrinformation, platelet activation, and/or platelet aggregation). The term“thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, and thromboembolic disorders in the chambersof the heart. The term “thromboembolic disorders” as used herein alsoincludes specific disorders selected from, but not limited to, unstableangina or other acute coronary syndromes, first or recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom (a) prosthetic valves or other implants, (b) indwelling catheters,(c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis. It is noted that thrombosis includes occlusion(e.g. after a bypass) and reocclusion (e.g., during or afterpercutaneous transluminal coronary angioplasty). The thromboembolicdisorders may result from conditions including but not limited toatherosclerosis, surgery or surgical complications, prolongedimmobilization, arterial fibrillation, congenital thrombophilia, cancer,diabetes, effects of medications or hormones, and complications ofpregnancy. The anticoagulant effect of compounds of the presentinvention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors offactor Xa was determined using purified human factor Xa and syntheticsubstrate. The rate of factor Xa hydrolysis of chromogenic substrateS2222 (Diapharma/Chromogenix, West Chester, Ohio) was measured both inthe absence and presence of compounds of the present invention.Hydrolysis of the substrate resulted in the release of pNA, which wasmonitored spectrophotometrically by measuring the increase in absorbanceat 405 nM. A decrease in the rate of absorbance change at 405 nm in thepresence of inhibitor is indicative of enzyme inhibition. The results ofthis assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant,K_(m), for substrate hydrolysis was determined at 25° C. using themethod of Lineweaver and Burk. Values of K_(i) were determined byallowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, SouthBend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presenceof inhibitor. Reactions were allowed to go for 30 minutes and thevelocities (rate of absorbance change vs time) were measured in the timeframe of 25-30 minutes. The following relationship was used to calculateK_(i) values:(v _(o) −v _(s))/v _(s) =I/(K_(i)(1+S/K _(m)))where:

-   -   v_(o) is the velocity of the control in the absence of        inhibitor;    -   v_(s) is the velocity in the presence of inhibitor;    -   I is the concentration of inhibitor;    -   K_(i) is the dissociation constant of the enzyme:inhibitor        complex;    -   S is the concentration of substrate;    -   K_(m) is the Michaelis constant.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K_(i)'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM. Using the methodologydescribed above, a number of compounds of the present invention werefound to exhibit K_(i)'s of ≦10 μM, thereby confirming the utility ofthe compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can bedemonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. Inthis model, rabbits weighing 2-3 kg anesthetized with a mixture ofxylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. Asaline-filled AV shunt device is connected between the femoral arterialand the femoral venous cannulae. The AV shunt device consists of a pieceof 6-cm tygon tubing that contains a piece of silk thread. Blood willflow from the femoral artery via the AV-shunt into the femoral vein. Theexposure of flowing blood to a silk thread will induce the formation ofa significant thrombus. After forty minutes, the shunt is disconnectedand the silk thread covered with thrombus is weighed. Test agents orvehicle will be given (i.v., i.p., s.c., or orally) prior to the openingof the AV shunt. The percentage inhibition of thrombus formation isdetermined for each treatment group. The ID₅₀ values (dose whichproduces 50% inhibition of thrombus formation) are estimated by linearregression.

The compounds of the present invention may also be useful as inhibitorsof serine proteases, notably human thrombin, Factor VIIa, Factor IXa,Factor XIa, urokinase, plasma kallikrein and plasmin. Because of theirinhibitory action, these compounds are indicated for use in theprevention or treatment of physiological reactions, blood coagulationand inflammation, catalyzed by the aforesaid class of enzymes.Specifically, the compounds have utility as drugs for the treatment ofdiseases arising from elevated thrombin activity such as myocardialinfarction, and as reagents used as anticoagulants in the processing ofblood to plasma for diagnostic and other commercial purposes.

Some compounds of the present invention were shown to be direct actinginhibitors of the serine protease thrombin by their ability to inhibitthe cleavage of small molecule substrates by thrombin in a purifiedsystem. In vitro inhibition constants were determined by the methoddescribed by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990),herein incorporated by reference. In these assays, thrombin-mediatedhydrolysis of the chromogenic substrate S2238 (Helena Laboratories,Beaumont, Tex.) was monitored spectrophotometrically. Addition of aninhibitor to the assay mixture results in decreased absorbance and isindicative of thrombin inhibition. Human thrombin (Enzyme ResearchLaboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000,was incubated with various substrate concentrations ranging from 0.20 to0.02 mM. After 25 to 30 minutes of incubation, thrombin activity wasassayed by monitoring the rate of increase in absorbance at 405 nm thatarises owing to substrate hydrolysis. Inhibition constants were derivedfrom reciprocal plots of the reaction velocity as a function ofsubstrate concentration using the standard method of Lineweaver andBurk. Using the methodology described above, some compounds of thisinvention were evaluated and found to exhibit a K_(i) of less than 10μm, thereby confirming the utility of the compounds of the presentinvention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, thrombin inhibitors, orthrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of the present invention that, when administeredalone or in combination with an additional therapeutic agent to amammal, is effective to prevent or ameliorate the thromboembolic diseasecondition or the progression of the disease.

By “administered in combination” or “combination therapy” it is meantthat a compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect. Other anticoagulant agents (or coagulation inhibitory agents)that may be used in combination with the compounds of this inventioninclude warfarin and heparin (either unfractionated heparin or anycommercially available low molecular weight heparin), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatrobanas well as other factor Xa inhibitors such as those describedin the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example byinhibiting the aggregation, adhesion or granular secretion of platelets.Agents include, but are not limited to, the various known non-steroidalanti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen,sulindac, indomethacin, mefenamate, droxicam, diclofenac,sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts orprodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA)and piroxicam are preferred. Other suitable platelet inhibitory agentsinclude IIb/IIIa antagonists (e.g., tirofiban, eptifibatide, andabciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A2-synthetase inhibitors, PDE-III inhibitors (e.g.,dipyridamole), and pharmaceutically acceptable salts or prodrugsthereof.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, is also intended to include ADP (adenosine diphosphate) receptorantagonists, preferably antagonists of the purinergic receptors P₂Y₁ andP₂Y₁₂, with P₂Y₁₂ being even more preferred. Preferred P₂Y₁₂ receptorantagonists include ticlopidine and clopidogrel, includingpharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is aneven more preferred agent. Ticlopidine and clopidogrel are alsopreferred compounds since they are known to be gentle on thegastro-intestinal tract in use.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the granular secretion of plasminogen activator inhibitor-1and/or serotonin) and/or fibrin formation are disrupted. A number ofthrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin, argatroban, andmelagatran, including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminal α-aminoboronicacid derivatives of lysine, ornithine, arginine, homoarginine andcorresponding isothiouronium analogs thereof. The term hirudin, as usedherein, includes suitable derivatives or analogs of hirudin, referred toherein as hirulogs, such as disulfatohirudin. The term thrombolytics orfibrinolytic agents (or thrombolytics or fibrinolytics), as used herein,denote agents that lyse blood clots (thrombi). Such agents includetissue plasminogen activator (natural or recombinant) and modified formsthereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK),lanoteplase (nPA), factor VIIa inhibitors, PAI-1 inhibitors (i.e.,inactivators of tissue plasminogen activator inhibitors),alpha2-antiplasmin inhibitors, and anisoylated plasminogen streptokinaseactivator complex, including pharmaceutically acceptable salts orprodrugs thereof. The term anistreplase, as used herein, refers toanisoylated plasminogen streptokinase activator complex, as described,for example, in EP 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable anti-arrythmic agents for use in combination withthe present compounds include: Class I agents (such as propafenone);Class II agents (such as carvadiol and propranolol); Class III agents(such as sotalol, dofetilide, amiodarone, azimilide and ibutilide);Class IV agents (such as ditiazem and verapamil); K⁺ channel openerssuch as I_(Ach) inhibitors, and I_(Kur) inhibitors (e.g., compounds suchas those disclosed in WO01/40231).

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include: alpha adrenergicblockers; beta adrenergic blockers; calcium channel blockers (e.g.,diltiazem, verapamil, nifedipine, amlodipine and mybefradil); diruetics(e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, spironolactone); renin inhibitors; ACEinhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutralendopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat, gemopatrilat and nitrates).

Examples of suitable calcium channel blockers (L-type or T-type) for usein combination with the compounds of the present invention includediltiazem, verapamil, nifedipine, amlodipine and mybefradil.

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable diruetics for use in combination with the compoundsof the present invention include: chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetanide, triamtrenene, amiloride, and spironolactone.

Examples of suitable mineralocorticoid receptor antagonists for use incombination with the compounds of the present invention includesprionolactone and eplirinone.

Examples of suitable phospodiesterase inhibitors for use in combinationwith the compounds of the present invention include: PDE III inhibitors(such as cilostazol); and PDE V inhibitors (such as sildenafil).

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include: HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (a.k.a.itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (a.k.a.rosuvastatin, or atavastatin or visastatin)); squalene synthetaseinhibitors; fibrates; bile acid sequestrants (such as questran); ACATinhibitors; MTP inhibitors; lipooxygenase inhibitors; cholesterolabsorption inhibitors; and cholesterol ester transfer protein inhibitors(e.g., CP-529414).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: biguanides (e.g.,metformin); glucosidase inhibitors (e.g., acarbose); insulins (includinginsulin secretagogues or insulin sensitizers); meglitinides (e.g.,repaglinide); sulfonylureas (e.g., glimepiride, glyburide andglipizide); biguanide/glyburide combinations (e.g., glucovance),thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein(aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1(GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable anti-depressant agents for use in combination withthe compounds of the present invention include nefazodone andsertraline.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include: prednisone;dexamethasone; enbrel; protien tyrosine kinase (PTK) inhibitors;cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2inhibitors); aspifrin; indomethacin; ibuprofen; prioxicam; naproxen;celecoxib; and/or rofecoxib.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate andraloxifene.

Examples of suitable hormone replacement therapies for use incombination with the compounds of the present invention include estrogen(e.g., congugated estrogens) and estradiol.

Examples of suitable anti-coagulants for use in combination with thecompounds of the present invention include heparins (e.g., unfractionedand low molecular weight heparins such as enoxaparin and dalteparin).

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include orlistat and aP2 inhibitors(such as those disclosed in WO00/59506).

Examples of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, and hydroxyzine pamoate.

Examples of suitable anti-proliferative agents for use in combinationwith the compounds of the present invention include cyclosporin A,paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.

Examples of suitable anti-ulcer and gastroesophageal reflux diseaseagents for use in combination with the compounds of the presentinvention include famotidine, ranitidine, and omeprazole.

Administration of the compounds of the present invention (i.e., a firsttherapeutic agent) in combination with at least one additionaltherapeutic agent (i.e., a second therapeutic agent), preferably affordsan efficacy advantage over the compounds and agents alone, preferablywhile permitting the use of lower doses of each (i.e., a synergisticcombination). A lower dosage minimizes the potential of side effects,thereby providing an increased margin of safety. It is preferred that atleast one of the therapeutic agents is administered in a sub-therapeuticdose. It is even more preferred that all of the therapeutic agents beadministered in sub-therapeutic doses. Sub-therapeutic is intended tomean an amount of a therapeutic agent that by itself does not give thedesired therapeutic effect for the condition or disease being treated.Synergistic combination is intended to mean that the observed effect ofthe combination is greater than the sum of the individual agentsadministered alone.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of factor Xa. Such compoundsmay be provided in a commercial kit, for example, for use inpharmaceutical research involving factor Xa. For example, a compound ofthe present invention could be used as a reference in an assay tocompare its known activity to a compound with an unknown activity. Thiswould ensure the experimenter that the assay was being performedproperly and provide a basis for comparison, especially if the testcompound was a derivative of the reference compound. When developing newassays or protocols, compounds according to the present invention couldbe used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving factor Xa. For example, the presence of factor Xa in anunknown sample could be determined by addition of chromogenic substrateS2222 to a series of solutions containing test sample and optionally oneof the compounds of the present invention. If production of pNA isobserved in the solutions containing test sample, but not in thepresence of a compound of the present invention, then one would concludefactor Xa was present.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic disorder (as definedpreviously). In another embodiment, the package insert states that thepharmaceutical composition can be used in combination (as definedpreviously) with a second therapeutic agent to treat a thromboembolicdisorder. The article of manufacture can further comprise: (d) a secondcontainer, wherein components (a) and (b) are located within the secondcontainer and component (c) is located within or outside of the secondcontainer. Located within the first and second containers means that-the respective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl-or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P, and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of a compound of the present invention and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to 25 milligrams of acompound of the present invention and about 50 to 150 milligrams of theanti-platelet agent, preferably about 0.1 to 1 milligrams of a compoundof the present invention and about 1 to 3 milligrams of antiplateletagents, per kilogram of patient body weight.

Where the compounds of Formula I are administered in combination withthrombolytic agent, typically a daily dosage may be about 0.1 to 1milligrams of the compound of Formula I, per kilogram of patient bodyweight and, in the case of the thrombolytic agents, the usual dosage ofthe thrombolyic agent when administered alone may be reduced by about70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when a compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but ratheR is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

1. A compound of formula Ic:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;the central lactam ring is substituted with 0-2 R^(1a); G is a group offormula IIa or IIb:

ring D, including the two atoms of ring E to which it is attached, is a5-6 membered ring consisting of: carbon atoms and 0-2 heteroatomsselected from the group consisting of N, O, and S(O)_(p); ring D issubstituted with 0-2 R and there are 0-3 ring double bonds; E isselected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl,and is substituted with 1-3 R; alternatively, ring D is absent, and ringE is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, triazolyl,thienyl, and thiazolyl, and ring E is substituted with 1-3 R;alternatively, ring D is absent, ring E is selected from phenyl, phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl,imidazolyl, isoxazolyl, oxazolyl, triazolyl, thienyl, and thiazolyl, andring E is substituted with 1 R and with a 5-6 membered heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p), wherein the 5-6 membered heterocycleis substituted with 0-2 carbonyls and 1-2 R and has 0-3 ring doublebonds; R is selected from H, C₁₋₄ alkyl, F, Cl, Br, I, OH, OCH₃,OCH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₃, CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹,NR⁸CH(═NR⁷), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, C(═NH)NH₂, CH₂NH₂,CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃ alkyl)₂, CH₂CH₂NH₂, CH₂CH₂NH(C₁₋₃ alkyl),CH₂CH₂N(C₁₋₃ alkyl)₂, (CR⁸R⁹)_(t)C(O)H, (CR⁸R⁹)_(t)C(O)R^(2c),(CR⁸R⁹)_(t)NR⁷R⁸, (CR⁸R⁹)_(t)C(O)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷C(O)R⁷,(CR⁸R⁹)_(t)OR³, (CR⁸R⁹)_(t)S(O)_(p)NR⁷R⁸, (CR⁸R⁹)_(t)NR⁷S(O)_(p)R⁷,(CR⁸R⁹)_(t)SR³, (CR⁸R⁹)_(t)S(O)R³, (CR⁸R⁹)_(t)S(O)₂R³, and OCF₃;alternatively, when 2 R groups are attached to adjacent atoms, theycombine to form methylenedioxy or ethylenedioxy; G₁ is selected from H,(CR³R^(3a))₁₋₂C(O)R², (CR³R^(3a))₁₋₂NR²R^(2a), (CR³R^(3a))₁₋₂OR²,(CR³R^(3a))₁₋₂S(O)_(p)R², (CR³R^(3a))₁₋₂NR²C(O)R²,(CR³R^(3a))₁₋₂NR²C(O)NR²R^(2a), (CR³R^(3a))₁₋₂NR²C(O)OR²,(CR³R^(3a))₁₋₂S(O)₂NR²R^(2a), (CR³R^(3a))₁₋₂NR²S(O)₂NR²R^(2a),(CR³R^(3a))₁₋₂OC(O)R², (CR³R^(3a))₁₋₂C(O)OR²,(CR³R^(3a))₁₋₂C(O)NR²R^(2a),(CR³R^(3a))₁₋₂C(O)NR²(CR³R^(3a))(CR³R^(3a))₁₋₂OR²,(CR³R^(3a))₁₋₂C(O)NR²(CR³R^(3a))(CR³R^(3a))₁₋₂NR²R^(2a),(CR³R^(3a))C(O)NR²(CR³R^(3a))₁₋₂C(O)NR²R^(2a),(CR³R^(3a))C(O)NR²(CR³R^(3a))₁₋₂C(O)OR², C₁₋₆ alkyl substituted with 0-2R^(1a), C₂₋₆ alkenyl substituted with 0-2 R^(1a), C₂₋₆ alkynylsubstituted with 0-2 R^(1a), (CR³R^(3a))₀₋₄—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(1a), and (CR³R^(3a))₀₋₄-5-12 membered heterocycle consistingof: carbon atoms and 1-4 heteroatoms selected from the group consistingof N, O, and S(O)_(p) and substituted with 0-3 R^(1a); A is selectedfrom: C₃₋₁₀ carbocycle substituted with 0-2 R⁴, and 5-12 memberedheterocycle consisting of: carbon atoms and 1-4 heteroatoms selectedfrom the group consisting of N, O, and S(O)_(p) and substituted with 0-2R⁴; B is selected from X—Y—R^(4a), N(B¹)C(O)C(R³R^(3g))₁₋₄NB²B³, and

provided that the central lactam ring and B are attached to differentatoms on A and that the A-X—N moiety forms other than a N—N—N group; B¹is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —(CH₂)₀₋₂—C₃₋₇ carbocyclesubstituted with 0-2 R^(4b), and —(CH₂)₀₋₂-5-6 membered heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b); B² isselected from H, C₁₋₆ alkyl substituted with 0-2 R^(4c), C(O)R^(2e),C(O)OR^(2d), C(O)NR^(2d)R^(2d), C(O)NH(CH₂)₂NR^(2d)R^(2d),SO₂NR^(2d)R^(2d), C(O)NHSO₂—C₁₋₄ alkyl, and S(O)_(p)R^(5a); B³ isselected from H, C₁₋₆ alkyl substituted with 0-2 R^(4c), —(CH₂)₀₋₂-3-6membered carbocycle substituted with 0-2 R⁵, and a —(CH₂)₀₋₂-4-6membered heterocycle consisting of: carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-2 R⁵; alternatively, NB²B³ is a 3-8 membered heterocycleconsisting of: the shown N, carbon atoms, and 0-3 additional heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-2 R⁵; ring Q is a 4-7 membered lactam consisting of, in additionto the amide group shown, carbon atoms and 0-2 heteroatoms selected fromNR^(4c), O, S, S(O), and S(O)₂, wherein: 0-2 double bonds are presentwithin the ring and the ring is substituted with 0-2 R^(4a);alternatively, ring Q is a 4-7 membered lactam to which another ring isfused, wherein: the lactam consists of, in addition to the shown amidegroup, carbon atoms and 0-2 heteroatoms selected from NR^(4c), O, S,S(O), and S(O)₂ and 0-2 double bonds are present within the ring; thefusion ring is phenyl or a 5-6 membered heteroaromatic consisting ofcarbon atoms and 0-2 NR^(4c), O, S, S(O), and S(O)₂; ring Q, whichincludes the lactam ring and the fusion ring, is substituted with 0-3R^(4a); X is absent or is selected from —(CR²R^(2a))₁₋₄—,—CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR^(1b))—, —CR²(NR^(1b)R²)—,—CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)—,—S(O)₂—, —SCR²R^(2a)—, —S(O)CR²R^(2a)—, —S(O)₂CR²R^(2a)—, —CR²R^(2a)S—,—CR²R^(2a)S(O)—, —CR²R^(2a)S(O)₂—, —S(O)₂NR²—, —S(O)₂NR²CR²R^(2a)—,—CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂—, —CR²R^(2a)NR²S(O)₂—,—NR²S(O)₂CR²R^(2a)—, —NR²C(O)—, —C(O)NR²—, —NR²C(O)CR²R^(2a)—,—C(O)NR²CR²R^(2a)—, —CR²R^(2a)NR²C(O)—, —CR²R^(2a)C(O)NR²—, NR²,—NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —OCR²R^(2a)—, and —CR²R^(2a)O—; Y isselected from CY¹Y²R^(4a), a C₃₋₁₀ carbocycle, and 3-10 memberedheterocycle, wherein the carobocycle or heterocycle consists of carbonatoms and 0-4 heteroatoms selected from N, O, and S(O)_(p), thecarbocycle or heterocycle further comprises 0-4 double bonds and 0-2carbonyl groups, and the carbocycle or heterocycle is substituted with0-2 R⁴; Y¹ and Y² are independently C₁₋₄ alkyl substituted with 0-2 R⁴;R^(1a), at each occurrence, is selected from H, —(CR³R^(3a))_(r)—R^(1b),—(CR³R^(3a))_(r)—CR³R^(1b)R^(1b),—(CR³R^(3a))_(r)—O—(CR³R^(3a))_(r)—R^(1b), —C₂₋₆ alkenylene-R^(1b),—C₂₋₆ alkynylene-R^(1b), —(CR³R^(3a))_(r)—C(═NR^(1b))NR³R^(1b),NR³(CR³R^(3a))_(t)R^(1c), O(CR³R^(3a))_(t)R^(1c),(CR³R^(3a))_(r)SCR³R^(3a)R^(1c),(CR³R^(3a))_(r)NR³(CR³R^(3a))_(r)R^(1b), (CR³R^(3a))_(r)C(O)NR²(CR³R^(3a))_(r)R^(1b), CO₂(CR³R^(3a))_(t)R^(1b),O(CR³R^(3a))_(t)R^(1b), (CR³R^(3a))_(r)S(CR³R^(3a))_(r)R^(1b),S(O)_(p)(CR³R^(3a))_(r)R^(1d), O(CR³R^(3a))_(r)R^(1d),NR³(CR³R^(3a))_(r)R^(1d), OC(O)NR³ (CR³R^(3a))_(r)R^(1d),NR³C(O)NR³(CR³R^(3a))_(r)R^(1d), NR³C(O)O(CR³R^(3a))_(r)R^(1d), andNR³C(O)(CR³R^(3a))_(r)R^(1d), provided that R^(1a) forms other than anN-halo, N—S, O—O, or N—CN bond; alternatively, when two R^(1a) groupsare attached to the same carbon atom, together with the carbon atom towhich they are attached they form a 3-10 membered carbocyclic orheterocyclic ring consisting of: carbon atoms and 0-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p), this ringbeing substituted with 0-2 R⁴ and 0-3 ring double bonds; R^(1b) isselected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —NO₂, —CHO,(CF₂)_(r)CF₃, (CR³R^(3a))_(r)OR², NR²R^(2a), C(O)R^(2b), CO₂R^(2b),OC(O)R², (CF₂)_(r)CO₂R^(2a), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR²,C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), NR²C(O)₂R^(2a),OC(O)NR²R^(2a), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂R², C(O)NR²SO₂R², SO₂R²C(O)NR², SO₂NR²C(O)R²,C₃₋₁₀ carbocycle substituted with 0-2 R⁴, and 4-10 membered heterocycleconsisting of carbon atoms and from 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p) and substituted with 0-2 R⁴,provided that R^(1b) forms other than an O—O, N-halo, N—S, or N—CN bond;R^(1c) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a),S(O)R², S(O)₂R², and SO₂NR²R^(2a); R^(1d) is selected from C₃₋₆carbocycle substituted with 0-2 R^(4b) and 5-10 membered heterocycleconsisting of carbon atoms and from 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p) and substituted-with 0-2 R^(4b),provided that R^(1d) forms other than an N—S bond; R², at eachoccurrence, is selected from H, CF₃, C₁₋₆ alkyl substituted with 0-2R^(4b), benzyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(4b),and —(CH₂)_(r)-5-10 membered heterocycle consisting of: carbon atoms and1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p)and substituted with 0-2 R^(4b); R^(2a), at each occurrence, is selectedfrom H, CF₃, C₁₋₆ alkyl substituted with 0-2 R^(4b), benzyl,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(4b), and—(CH₂)_(r)-5-10 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-2 R^(4b); alternatively, R² and R^(2a), together withthe atom to which they are attached, combine to form a 5 or 6 memberedsaturated, partially saturated or unsaturated ring substituted with 0-2R^(4b) and consisting of: 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S(O)_(p); R^(2b), at each occurrence, isselected from CF₃, C₁₋₄ alkoxy substituted with 0-2 R^(4b), C₁₋₆ alkylsubstituted with 0-2 R^(4b), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-2 R^(4b), and —(CH₂)_(r)-5-10 membered heterocycle consisting of:carbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p) and substituted with 0-2 R^(4b); R^(2c), at eachoccurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(4b), and—(CH₂)_(r)-5-10 membered heterocycle containing from 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-2 R^(4b); R^(2d), at each occurrence, is selected from H, R^(4c),C₁₋₆ alkyl substituted with 0-2 R^(4c), —(CR³R^(3a))_(r)—C₃₋₁₀carbocycle substituted with 0-2 R^(4c), and —(CR³R^(3a))_(r)-5-10membered heterocycle substituted with 0-2 R^(4c) and consisting of:carbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), provided that R^(2d) forms other than a N-halo,N-C-halo, S(O)_(p)-halo, O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O, O—N,O—S, or O—O moiety; alternatively, when two R^(2d)'s are attached to thesame nitrogen atom, then R^(2d) and R^(2d), together with the nitrogenatom to which they are attached, combine to form a 5-10 memberedsaturated, partially saturated or unsaturated ring substituted with 0-2R^(4b) and consisting of: 0-1 additional heteroatoms selected from thegroup consisting of N, O, and S(O)_(p); R^(2e), at each occurrence, isselected from H, R^(4c), C₁₋₆ alkyl substituted with 0-2 R^(4c),—(CR³R^(3a))_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(4c), and—(CR³R^(3a))_(r)-5-10 membered heterocycle substituted with 0-2 R^(4c)and consisting of: carbon atoms and 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p), provided that R^(2e) forms otherthan a C(O)-halo or C(O)—S(O)_(p) moiety; R³, at each occurrence, isselected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, and phenyl; R^(3a), at eachoccurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, and phenyl;alternatively, R³ and R^(3a), together with the nitrogen atom to whichthey are attached, combine to form a 5 or 6 membered saturated,partially unsaturated, or unsaturated ring consisting of: carbon atoms,the nitrogen atom to which R³ and R^(3a) are attached, and 0-1additional heteroatoms selected from the group consisting of N, O, andS(O)_(p); R^(3b), at each occurrence, is selected from H, C₁₋₆ alkylsubstituted with 0-2 R^(1a), C₂₋₆ alkenyl substituted with 0-2 R^(1a),C₂₋₆ alkynyl substituted with 0-2 R^(1a), —(C₀₋₄ alkyl)-5-10 memberedcarbocycle substituted with 0-3 R^(1a), and —(C₀₋₄ alkyl)-5-10 memberedheterocycle substituted with 0-3 R^(1a) and consisting of: carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p); R^(3c), at each occurrence, is selected from CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃,benzyl, and phenyl; R^(3d), at each occurrence, is selected from H, CH₃,CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,C₁₋₄ alkyl-phenyl, and C(═O)R^(3c); R^(3g), at each occurrence, isselected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —(CH₂)_(r)-3-6 membered carbocycle,and —(CH₂)_(r)-5-6 membered heterocycle consisting of: carbon atoms and1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p); alternatively, when R³ and R^(3g) are attached to the samecarbon atom, they combine with the attached carbon atom to form acyclopropyl group; R⁴, at each occurrence, is selected from H, ═O,(CR³R^(3a))_(r)OR², (CR³R^(3a))_(r)F, (CR³R^(3a))_(r)Cl,(CR³R^(3a))_(r)Br, (CR³R^(3a))_(r)I, C₁₋₄ alkyl, (CR³R^(3a))_(r)CN,(CR³R^(3a))_(r)NO₂, (CR³R^(3a))_(r)NR²R^(2a), (CR³R^(3a))_(r)C(O)R^(2c),(CR³R^(3a))_(r)NR²C(O)R^(2b), (CR³R^(3a))_(r)C(O)NR²R^(2a),(CR³R^(3a))_(r)NR²C(O)NR²R^(2a), (CR³R^(3a))_(r)C(═NR²)NR²R^(2a),(CR³R^(3a))_(r)C(═NS(O)₂R⁵)NR²R^(2a),(CR³R^(3a))_(r)NR²C(═NR²)NR²R^(2a),(CR³R^(3a))_(r)C(O)NR²C(═NR²)NR²R^(2a), (CR³R^(3a))_(r)SO₂NR²R^(2a),(CR³R^(3a))_(r)NR²SO₂NR²R^(2a), (CR³R^(3a))_(r)NR²SO₂—C₁₋₄ alkyl,(CR³R^(3a))_(r)NR²SO₂R⁵, (CR³R^(3a))_(r)S(O)_(p)R^(5a),(CR³R^(3a))_(r)(CF₂)_(r)CF₃, NHCH₂R^(1b), OCH₂R^(1b), SCH₂R^(1b),NH(CH₂)₂(CH₂)_(t)R^(1b), O(CH₂)₂(CH₂)_(t)R^(1b), S(CH₂)₂(CH₂)_(t)R^(1b),(CR³R^(3a))_(r)-5-6 membered carbocycle substituted with 0-1 R⁵, and a(CR³R^(3a))_(r)-5-6 membered heterocycle consisting of: carbon atoms and1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p)and substituted with 0-1 R⁵; R^(4a) is selected from C₁₋₆ alkylsubstituted with 0-2 R^(4c), C₂₋₆ alkenyl substituted with 0-2 R^(4c),C₂₋₆ alkynyl substituted with 0-2 R^(4c), —(CR³R^(3g))_(r)—C₅₋₁₀membered carbocycle substituted with 0-3 R^(4c), —(CR³R^(3g))_(r)-5-10membered heterocycle substituted with 0-3 R^(4c) and consisting of:carbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), (CR³R^(3g))_(r)CN,(CR³R^(3g))_(r)C(═NR^(2d))NR^(2d)R^(2d),(CR³R^(3g))_(r)NR^(2d)C(═NR^(2d))NR^(2d)R^(2d),(CR³R^(3g))_(r)NR^(2d)C(R^(2e))(═NR^(2d)), (CR³R^(3g))_(r)NR^(2d)R^(2d),(CR³R^(3g))_(r)N(→O)R^(2d)R^(2d), (CR³R^(3g))_(r)OR^(2d),(CR³R^(3g))_(r)—NR^(2d)C(O)R^(2e), (CR³R^(3g))_(r)—C(O)R^(2e),(CR³R^(3g))_(r)—OC(O)R^(2e), (CR³R^(3g))_(r)—C(O)NR^(2d)R^(2d),(CR³R^(3g))_(r)—C(O)OR^(2d), (CR³R^(3g))_(r)—NR^(2d)C(O)NR^(2d)R^(2d),(CR³R^(3g))_(r)—OC(O)NR^(2d)R^(2d), (CR³R^(3g))_(r)—NR^(2d)C(O)OR^(2d),(CR³R^(3g))_(r)—SO₂NR^(2d)R^(2d),(CR³R^(3g))_(r)—NR^(2d)SO₂NR^(2d)R^(2d),(CR³R^(3g))_(r)—C(O)NR^(2d)SO₂R^(2d), (CR³R^(3g))_(r)—NR^(2d)SO₂R^(2d),and (CR³R^(3g))_(r)—S(O)_(p)R^(2d), provided that S(O)_(p)R^(2d) formsother than S(O)₂H or S(O)H and further provided that R^(4a) is otherthan a hydroxamic acid; R^(4b), at each occurrence, is selected from H,═O, (CH₂)_(r)OR³, (CH₂)_(r)F, (CH₂)_(r)Cl, (CH₂)_(r)Br, (CH₂)_(r)I, C₁₋₄alkyl, (CH₂)_(r)CN, (CH₂)_(r)NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), (CH₂)_(r)NR³C(O)R^(3a), (CH₂)_(r)—C(O)NR³R^(3a),(CH₂)_(r)NR³C(O)NR³R^(3a), (CH₂)_(r)—C(═NR³)NR³R^(3a),(CH₂)_(r)NR³C(═NR³)NR³R^(3a), (CH₂)_(r)SO₂NR³R^(3a),(CH₂)_(r)NR³SO₂NR³R^(3a), (CH₂)_(r)NR³SO₂—C₁₋₄ alkyl, (CH₂)_(r)NR³SO₂CF₃, (CH₂)_(r)NR³SO₂-phenyl, (CH₂)_(r)S(O)_(p)CF₃,(CH₂)_(r)S(O)_(p)—C₁₋₄ alkyl, (CH₂)_(r)S(O)_(p)-phenyl, and(CH₂)_(r)(CF₂)_(r)CF₃; R^(4c), at each occurrence, is selected from ═O,(CR³R^(3a))_(r)OR², (CR³R^(3a))_(r)F, (CR³R^(3a))_(r)Br,(CR³R^(3a))_(r)Cl, (CR³R^(3a))_(r)CF₃, C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CR³R^(3a))_(r)CN, (CR³R^(3a))_(r)NO₂,(CR³R^(3a))_(r)NR²R^(2a), (CR³R^(3a))_(r)N(→O)R²R^(2a),(CR³R^(3a))_(r)C(O)R^(2c), (CR³R^(3a))_(r)NR²C(O)R^(2b),(CR³R^(3a))_(r)C(O)NR²R^(2a), (CR³R^(3a))_(r)N═CHOR³,(CR³R^(3a))_(r)C(O)NR²(CH₂)₂NR²R^(2a), (CR³R^(3a))_(r)NR²C(O)NR²R^(2a),(CR³R^(3a))_(r)C(═NR²)NR²R^(2a), (CR³R^(3a))_(r)NR²C(═NR²)NR²R^(2a),(CR³R^(3a))_(r)SO₂NR²R^(2a), (CR³R^(3a))_(r)NR²SO₂NR²R^(2a),(CR³R^(3a))_(r)C(O)NR²SO₂—C₁₋₄ alkyl, (CR³R^(3a))_(r)NR²SO₂R^(5a),(CR³R^(3a))_(r)C(O)NR²SO₂R^(5a), (CR³R^(3a))_(r)S(O)_(p)R^(5a),(CF₂)_(r)CF₃, (CR³R^(3a))_(r)C₃₋₁₀ carbocycle substituted with 0-2R^(4b), and (CR³R^(3a))_(r)4-10 membered heterocycle substituted with0-2 R^(4b) and consisting of carbon atoms and from 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p); R⁵, at eachoccurrence, is selected from H, C₁₋₆ alkyl, ═O, (CH₂)_(r)OR³, F, Cl, Br,I, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c),(CH₂)_(r)NR³C(O)R^(3a), (CH₂)_(r)C(O)NR³R^(3a),(CH₂)_(r)NR³C(O)NR³R^(3a), (CH₂)_(r)CH(═NOR^(3d)),(CH₂)_(r)C(═NR³)NR³R^(3a), (CH₂)_(r)NR³C(═NR³)NR³R^(3a),(CH₂)_(r)SO₂NR³R^(3a), (CH₂)_(r)NR³SO₂NR³R^(3a), (CH₂)_(r)NR³SO₂—C₁₋₄alkyl, (CH₂)_(r)NR³SO₂CF₃, (CH₂)_(r)NR³SO₂-phenyl, (CH₂)_(r)S(O)_(p)CF₃,(CH₂)_(r)S(O)_(p)—C₁₋₄ alkyl, (CH₂)_(r)S(O)_(p)-phenyl, (CF₂)_(r)CF₃,phenyl substituted with 0-2 R⁶, naphthyl substituted with 0-2 R⁶, andbenzyl substituted with 0-2 R⁶; R^(5a), at each occurrence, is selectedfrom C₁₋₆ alkyl, (CH₂)_(r)OR³, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³,(CH₂)_(r)C(O)OR^(3c), (CH₂)_(r)NR³C(O)R^(3a), (CH₂)_(r)C(O)NR³R^(3a),(CF₂)_(r)CF₃, phenyl substituted with 0-2 R⁶, naphthyl substituted with0-2 R⁶, and benzyl substituted with 0-2 R⁶, provided that R^(5a) doesnot form a S—N or S(O)_(p)—C(O) bond; R⁶, at each occurrence, isselected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂,(CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b),NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a),and NR²SO₂—C₁₋₄ alkyl; R⁷, at each occurrence, is selected from H, OH,C₁₋₆ alkyl, C₁₋₆ alkyl-C(O)—, —C₁₋₆ alkyl-O—, (CH₂)_(n)-phenyl, C₁₋₄alkyl-OC(O)—, C₆₋₁₀ aryl-O—, C₆₋₁₀ aryl-OC(O)—, C₆₋₁₀ aryl-CH₂—C(O)—,C₁₋₄ alkyl-C(O)O—C₁₋₄ alkyl-OC(O)—, C₆₋₁₀ aryl-C(O)O—C₁₋₄ alkyl-OC(O)—,C₁₋₆ alkyl-NH₂—C(O)—, phenyl-NH₂—C(O)—, and phenyl C₁₋₄ alkyl-C(O)—; R⁸,at each occurrence, is selected from H, C₁₋₆ alkyl, and(CH₂)_(n)-phenyl; alternatively, R⁷ and R⁸, when attached to the samenitrogen, combine to form a 5-10 membered heterocyclic ring consistingof carbon atoms and 0-2 additional heteroatoms selected from the groupconsisting of N, O, and S(O)_(p); R⁹, at each occurrence, is selectedfrom H, C₁₋₆ alkyl, and (CH₂)_(n)-phenyl; n, at each occurrence, isselected from 0, 1, 2, and 3; p, at each occurrence, is selected from 0,1, and 2; r, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and6; r1, at each occurrence, is selected from 1, 2, 3, 4, 5, and 6; and,t, at each occurrence, is selected from 0, 1, 2, and
 3. 2. A compoundaccording to claim 1, wherein: the central lactam ring is substitutedwith 0-1 R^(1a); G is a group of formula IIa or IIb:

ring D, including the two atoms of ring E to which it is attached, is a5-6 membered ring consisting of: carbon atoms and 0-2 heteroatomsselected from the group consisting of N, O, and S(O)_(p); ring D issubstituted with 0-2 R and there are 0-3 ring double bonds; E isselected from phenyl, pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl,and is substituted with 1-2 R; alternatively, ring D is absent, and ringE is selected from phenyl, pyridyl, pyrimidyl, and thienyl, and ring Eis substituted with 1-2 R; alternatively, ring D is absent, ring E isselected from phenyl, pyridyl, and thienyl, and ring E is substitutedwith a 5 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p),wherein the 5 membered heterocycle is substituted with 0-1 carbonyls and1-2 R and has 0-3 ring double bonds; R is selected from H, C₁₋₄ alkyl,F, Cl, OH, OCH₃, OCH₂CH₃, OCH(CH₃)₂, CN, C(═NH)NH₂, NH₂, NH(C₁₋₃ alkyl),N(C₁₋₃ alkyl)₂, C(═NH)NH₂, CH₂NH₂, CH₂NH(C₁₋₃ alkyl), CH₂N(C₁₋₃ alkyl)₂,(CR⁸R⁹)_(t)NR⁷R⁸, C(O)NR⁷R⁸, CH₂C(O)NR⁷R⁸, S(O)_(p)NR⁷R⁸,CH₂S(O)_(p)NR⁷R⁸, and OCF₃; alternatively, when 2 R groups are attachedto adjacent atoms, they combine to form methylenedioxy or ethylenedioxy;G₁ is selected from H, (CR³R^(3a))C(O)R², (CR³R^(3a))NR²R^(2a),(CR³R^(3a))OR², (CR³R^(3a))S(O)_(p)R², (CR³R^(3a))NR²C(O)R²,(CR³R^(3a))NR²C(O)NR²R^(2a), (CR³R^(3a))NR²C(O)OR²,(CR³R^(3a))S(O)₂NR²R^(2a), (CR³R^(3a))NR²S(O)₂NR²R^(2a),(CR³R^(3a))OC(O)R², (CR³R^(3a))C(O)OR², (CR³R^(3a))C(O)NR²R^(2a),(CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))OR²,(CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))(CR³R^(3a))OR²,(CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))NR²R^(2a),(CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))(CR³R^(3a))NR²R^(2a),(CR³R^(3a))C(O)NR²(CR³R^(3a))C(O)NR²R^(2a),(CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))C(O)NR²R^(2a),(CR³R^(3a))C(O)NR²(CR³R^(3a))C(O)OR²,(CR³R^(3a))C(O)NR²(CR³R^(3a))(CR³R^(3a))C(O)OR², C₁₋₆ alkyl substitutedwith 0-1 R^(1a), C₂₋₆ alkenyl substituted with 0-1 R^(1a), C₂₋₆ alkynylsubstituted with 0-1 R^(1a), (CR³R^(3a))₀₋₄—C₃₋₁₀ carbocycle substitutedwith 0-1 R^(1a), and (CR³R^(3a))₀₋₄-5-12 membered heterocycle consistingof: carbon atoms and 1-4 heteroatoms selected from the group consistingof N, O, and S(O)_(p) and substituted with 0-1 R^(1a); A is selectedfrom: C₅₋₁₀ carbocycle substituted with 0-2 R⁴, and 5-10 memberedheterocycle consisting of: carbon atoms and 1-4 heteroatoms selectedfrom the group consisting of N, O, and S(O)_(p) and substituted with 0-2R⁴; provided that A is other than a dihydro-benzopyran; B is selectedfrom N(B¹)C(O)C(R³R^(3g))NB²B³, N(B¹ )C(O)C(R³R^(3g))C(R³R^(3g))NB²B³,

and

provided that the central lactam ring and B are attached to differentatoms on A and that the A-X—N moiety forms other than a N—N—N group; B¹is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —(CH₂)₀₋₁—C₃₋₇ carbocyclesubstituted with 0-2 R^(4b), and —(CH₂)₀₋₁-5-6 membered heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b); B² isselected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, NR^(2d)R^(2d), CH₂—NR^(2d)R^(2d),CH₂CH₂—NR^(2d)R^(2d), C(O)R^(2e), C(O)NR^(2d)R^(2d), SO₂NR^(2d)R^(2d),and S(O)_(p)R^(5a); B³ is selected from H, C₁₋₆ alkyl substituted with0-1 R^(4c), —(CH₂)₀₋₁-3-6 membered carbocycle substituted with 0-1 R⁵,and a —(CH₂)₀₋₁-5-6 membered heterocycle consisting of: carbon atoms and1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p)and substituted with 0-1 R⁵; ring Q is a 4-7 membered lactam consistingof, in addition to the amide group shown, carbon atoms and 0-2heteroatoms selected from NR^(4c), O, S, S(O), and S(O)₂, wherein: 0-2double bonds are present within the ring and the ring is substitutedwith 0-2 R^(4a); alternatively, ring Q is a 4-7 membered lactam to whichanother ring is fused, wherein: the lactam consists of, in addition tothe shown amide group, carbon atoms and 0-2 heteroatoms selected fromNR^(4c), O, S, S(O), and S(O)₂ and 0-1 double bonds are present withinthe ring; the fusion ring is phenyl or a 5-6 membered heteroaromaticconsisting of carbon atoms and 0-2 NR^(4c), O, and S; ring Q, whichincludes the lactam ring and the fusion ring, is substituted with 0-3R^(4a); ring Q¹ is selected from CY¹Y², a C₃₋₇ monocyclic carbocycle,and a 3-7 membered monocyclic heterocycle, wherein the carbocycle orheterocycle consists of: carbon atoms and 0-2 heteroatoms selected fromN, O, and S(O)_(p), the carbocycle or heterocycle further comprises 0-2double bonds and 0-2 carbonyl groups, and the carbocycle or heterocycleis substituted with 0-2 R⁴; X is absent or is selected from—(CR²R^(2a))₁₋₄—, —C(O)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)₂—,—S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²C(O)—,—C(O)NR²—, NR², —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —OCR²R^(2a)—, and—CR²R^(2a)O—; Y¹ and Y² are independently C₁₋₃ alkyl substituted with0-1 R⁴; R^(1a), at each occurrence, is selected from H,—(CR³R^(3a))_(r)—R^(1b), —(CR³R^(3a))_(r)—O—(CR³R^(3a))_(r)—R^(1b),—C₂₋₆ alkenylene-R^(1b), —C₂₋₆ alkynylene-R^(1b),—(CR³R^(3a))_(r)—C(═NR^(1b))NR³R^(1b), NR³(CR³R^(3a))_(t)R^(1c),O(CR³R^(3a))_(t)R^(1c), (CR³R^(3a))_(r)SCR³R^(3a)R^(1c),(CR³R^(3a))_(r)NR³(CR³R^(3a))_(r)R^(1b),(CR³R^(3a))_(r)C(O)NR²(CR³R^(3a))_(r)R^(1b), CO₂(CR³R^(3a))_(t)R^(1b),O(CR³R^(3a))_(t)R^(1b), S(O)_(p)(CR³R^(3a))_(r)R^(1d),O(CR³R^(3a))_(r)R^(1d), NR³(CR³R^(3a))_(r)R^(1d),OC(O)NR³(CR³R^(3a))_(r)R^(1d), NR³C(O)NR³(CR³R^(3a))_(r)R^(1d),NR³C(O)O(CR³R^(3a))_(r)R^(1d), and NR³C(O)(CR³R^(3a))_(r)R^(1d),provided that R^(1a) forms other than an N-halo, N—S, O—O, or N—CN bond;alternatively, when two R^(1a) groups are attached to the same carbonatom, together with the carbon atom to which they are attached they forma 3-10 membered carbocyclic or heterocyclic ring consisting of: carbonatoms and 0-4 heteroatoms selected from the group consisting of N, O,and S(O)_(p), this ring being substituted with 0-2 R⁴ and 0-3 ringdouble bonds; R^(1b) is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, F, Cl, Br, I, —CN, —CHO, CF₃, (CR³R^(3a))_(r)OR², NR²R^(2a),C(O)R^(2b), CO₂R^(2b), OC(O)R², CO₂R^(2a), S(O)_(p)R², NR²(CH₂)_(r)OR²,NR²C(O)R^(2b), NR²C(O)NR²R^(2a), NR²C(O)₂R^(2a), OC(O)NR²R^(2a),C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂NR²R^(2a),NR²SO₂R², C(O)NR²SO₂R², SO₂NR²C(O)R², C₃₋₁₀ carbocycle substituted with0-2 R⁴, and 4-10 membered heterocycle consisting of carbon atoms andfrom 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p) and substituted with 0-2 R⁴, provided that R^(1b) forms otherthan an O—O, N-halo, N—S, or N—CN bond; R^(1c) is selected from H,CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a), S(O)R², S(O)₂R², andSO₂NR²R^(2a); R², at each occurrence, is selected from H, CF₃, CH₃,CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,C(CH₃)₃, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂, benzyl, C₅-₆carbocycle substituted with 0-2 R^(4b), a C₅₋₆ carbocyclic-CH₂ groupsubstituted with 0-2 R^(4b), a 5-6 membered heterocycle consisting of:carbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p) and substituted with 0-2 R^(4b), and a 5-6 memberedheterocycle-CH₂ group consisting of: carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-2 R^(4b) R^(2a), at each occurrence, is selected from H, CF₃,CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, C(CH₃)₃, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂,CH₂CH₂CH₂NMe₂, benzyl, C₅-₆ carbocycle substituted with 0-2 R^(4b), and5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-2 R^(4b); alternatively, R² and R^(2a), together with the atom towhich they are attached, combine to form a 5 or 6 membered saturated,partially saturated or unsaturated ring substituted with 0-2 R^(4b) andconsisting of: 0-1 additional heteroatoms selected from the groupconsisting of N, O, and S(O)_(p); R^(2b), at each occurrence, isselected from CF₃, C₁₋₄ alkoxy, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, benzyl, C₅₋₆carbocycle substituted with 0-2 R^(4b), and 5-6 membered heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b);R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, CH₃,CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,C(CH₃)₃, benzyl, C₅₋₆ carbocycle substituted with 0-2 R^(4b), and 5-6membered heterocycle containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b);R^(2d), at each occurrence, is selected from H, R^(4c), C₁₋₄ alkylsubstituted with 0-2 R^(4c), —(CR³R^(3a))_(r)—C₃₋₆ carbocyclesubstituted with 0-2 R^(4c), and —(CR³R^(3a))_(r)-5-6 memberedheterocycle substituted with 0-2 R^(4c) and consisting of: carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p), provided that R^(2d) forms other than a N-halo, N-C-halo,S(O)_(p)-halo, O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O, O—N, O—S, orO—O moiety; alternatively, when two R^(2d)'s are attached to the samenitrogen atom, then R^(2d) and R^(2d), together with the nitrogen atomto which they are attached, combine to form a 5 or 6 membered saturated,partially saturated or unsaturated ring substituted with 0-2 R^(4b) andconsisting of: 0-1 additional heteroatoms selected from the groupconsisting of N, O, and S(O)_(p); R^(2e), at each occurrence, isselected from H, R^(4c), C₁₋₄ alkyl substituted with 0-2 R^(4c),—(CR³R^(3a))_(r)—C₃₋₆ carbocycle substituted with 0-2 R^(4c), and—(CR³R^(3a))_(r)-5-6 membered heterocycle substituted with 0-2 R^(4c)and consisting of: carbon atoms and 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p), provided that R^(2e) forms otherthan a C(O)-halo or C(O)—S(O)_(p) moiety; R³, at each occurrence, isselected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl, and phenyl;R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, benzyl, and phenyl; alternatively, R³ and R^(3a), togetherwith the nitrogen atom to which they are attached, combine to form a 5or 6 membered saturated, partially unsaturated, or unsaturated ringconsisting of: carbon atoms and the nitrogen atom to which R³ and R^(3a)are attached; R^(3c), at each occurrence, is selected from CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, benzyl, and phenyl; R^(3d), at each occurrence, isselected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂-phenyl,CH₂CH₂-phenyl, and C(═O)R^(3c); R⁴, at each occurrence, is selected fromH, ═O, OR², CH₂OR², (CH₂)₂OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂,NR²R^(2a), CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b),C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, CF₃, CF₂CF₃, 5-6 memberedcarbocycle substituted with 0-1 R⁵, and a 5-6 membered heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) and substituted with 0-1 R⁵; R⁴, ateach occurrence, is selected from H, ═O, OR², CH₂OR², (CH₂)₂OR², F, Cl,Br, I, C₁₋₄ alkyl, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), (CH₂)₂NR²R^(2a),C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a),SO₂NR²R^(2a), NR²SO₂NR²R^(2a), S(O)_(p)R^(5a), NR²SO₂—C₁₋₄ alkyl,NR²SO₂R⁵, CF₃, CF₂CF₃, 5-6 membered carbocycle substituted with 0-1 R⁵,and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p),and substituted with 0-1 R⁵; R^(4b), at each occurrence, is selectedfrom H, ═O, OR³, CH₂OR³, F, Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR³R^(3a),CH₂NR³R^(3a), C(O)R³, CH₂—C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c),NR³C(O)R^(3a), CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂C(O)NR³R^(3a),NR³C(O)NR³R^(3a), CH₂NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a),CH₂C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), CH₂NR³C(═NR³)NR³R^(3a),SO₂NR³R^(3a), CH₂SO₂NR³R^(3a), NR³SO₂NR³R^(3a), CH₂NR³SO₂NR³R^(3a),NR³SO₂—C₁₋₄ alkyl, CH₂NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, CH₂NR³SO₂CF₃,NR³SO₂-phenyl, CH₂NR³SO₂-phenyl, S(O)_(p)CF₃, CH₂S(O)_(p)CF₃,S(O)_(p)—C₁₋₄ alkyl, CH₂S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl,CH₂S(O)_(p)-phenyl, CF₃, and CH₂—CF₃; R^(4c), at each occurrence, isselected from ═O, (CR³R^(3a))_(r)OR₂, (CR³R^(3a))_(r)F,(CR³R^(3a))_(r)Br, (CR³R^(3a))_(r)Cl, (CR³R^(3a))_(r)CF₃, C₁₋₄ alkyl,C₂₋₃ alkenyl, C₂₋₃ alkynyl, (CR³R^(3a))_(r)CN, (CR³R^(3a))_(r)NO₂,(CR³R^(3a))_(r)NR²R^(2a), (CR³R^(3a))_(r)N(→O)R²R^(2a),(CR³R^(3a))_(r)C(O)R^(2c), (CR³R^(3a))_(r)NR²C(O)R^(2b),(CR³R^(3a))_(r)C(O)NR²R^(2a), (CR³R^(3a))_(r)NR²C(O)NR²R^(2a),(CR³R^(3a))_(r)SO₂NR²R^(2a), (CR³R^(3a))_(r)NR²SO₂NR²R^(2a),(CR³R^(3a))_(r)NR²SO₂R^(5a), (CR³R^(3a))_(r)C(O)NR²SO₂R^(5a),(CR³R^(3a))_(r)S(O)_(p)R^(5a), (CF₂)_(r)CF₃, (CR³R^(3a))_(r)C₃₋₁₀carbocycle substituted-with 0-2 R^(4b), and (CR³R^(3a))_(r)5-10 memberedheterocycle consisting of carbon atoms and from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S(O)_(p) and substituted with 0-2R^(4b); R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃,OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a), C(O)R³,CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a),NR³C(O)NR³R^(3a), CH(═NOR^(3d)), C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a),SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃,NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)-C₁₋₄ alkyl, S(O)_(p)-phenyl, CF₃,phenyl substituted with 0-2 R⁶, naphthyl substituted with 0-2 R⁶, andbenzyl substituted with 0-2 R⁶; and, R^(5a), at each occurrence, isselected from CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, OR³, CH₂OR³, NR³R^(3a),CH₂NR³R^(3a), C(O)R³, CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c),NR³C(O)R^(3a), CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂C(O)NR³R^(3a), CF₃,CF₂CF₃, phenyl substituted with 0-2 R⁶, naphthyl substituted with 0-2R⁶, and benzyl substituted with 0-2 R⁶, provided that R^(5a) does notform a S—N or S(O)_(p)—C(O) bond; R⁶, at each occurrence, is selectedfrom H, OH, OR², F, Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂,NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl.
 3. Acompound according to claim 2, wherein the compound is of formula Ic: Gis selected from the group:

G₁ is selected from H, C₁₋₆ alkyl substituted with 0-1 R^(1a),CH₂C(O)OR², CH₂C(O)NR²R^(2a), CH₂C(O)NR²CH₂CH₂OR²,CH₂C(O)NR²CH₂CH₂NR²R^(2a), CH₂C(O)NR²CH₂C(O)NR²R^(2a),CH₂C(O)NR²CH₂CH₂C(O)NR²R^(2a), CH₂C(O)NR²CH₂C(O)OR², andCH₂C(O)NR²CH₂CH₂C(O)OR²; A is selected from one of the followingcarbocyclic and heterocyclic groups which are substituted with 0-2 R⁴;cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl,furanyl, morpholinyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl,benzothiofuranyl, indolinyl, indolyl, benzimidazolyl, benzoxazolyl,benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, andisoindazolyl; B¹ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,—(CH₂)₀₋₁—C₅₋₆ carbocycle substituted with 0-2 R^(4b), and —(CH₂)₀₋₁-5-6membered heterocycle consisting of: carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-2 R^(4b); B² is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, C(O)R^(2e), C(O)NR^(2d)R^(2d), SO₂NR^(2d)R^(2d), andS(O)_(p)R^(5a); B³ is selected from H, C₁₋₆ alkyl substituted with 0-1R^(4c), —(CH₂)₀₋₁-3-6 membered carbocycle substituted with 0-1 R⁵, and a—(CH₂)₀₋₁-5-6 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-1 R⁵; ring Q is a 5-7 membered lactam consisting of,in addition to the amide group shown, carbon atoms and 0-2 heteroatomsselected from NR^(4c), O, S, S(O), and S(O)₂, wherein: 0-2 double bondsare present within the ring and the ring is substituted with 0-2 R^(4a);alternatively, ring Q is a 5-7 membered lactam to which another ring isfused, wherein: the lactam consists of, in addition to the shown amidegroup, carbon atoms and 0-2 heteroatoms selected from NR^(4c), O, S,S(O), and S(O)₂ and 0-1 double bonds are present within the ring; thefusion ring is phenyl or a 5-6 membered heteroaromatic consisting ofcarbon atoms and 0-2 NR^(4c), O, and S; ring Q, which includes thelactam ring and the fusion ring, is substituted with 0-3 R^(4a); ring Q¹is selected from CY¹Y², a C₃₋₆ monocyclic carbocycle, and 5-6 memberedmonocyclic heterocycle, wherein the carobocycle or heterocycle consistsof carbon atoms and 0-2 heteroatoms selected from N, O, and S(O)_(p),the carbocycle or heterocycle further comprises 0-1 double bonds and 0-1carbonyl groups, and the carbocycle or heterocycle is substituted with0-2 R⁴; X is absent or is selected from —(CR²R^(2a))₁₋₂—, —C(O)—,—S(O)₂—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²C(O)—, —C(O)NR²—, NR²,—NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —OCR²R^(2a)—, and —CR²R^(2a)O—; Y¹and Y² are independently C₁₋₂ alkyl substituted with 0-1 R⁴; R^(1a), ateach occurrence, is selected from H, —(CH₂)_(r)R^(1b),—(CH₂)_(r)—O—(CH₂)_(r)—R^(1b), —(CH₂)_(r)—C(═NR^(1b))NR³R^(1b),NR³(CR³R^(3a))_(t)R^(1c), O(CR³R^(3a))_(t)R^(1c),(CH₂)_(r)NR³(CH₂)_(r)R^(1b), (CH₂)_(r)C(O)NR²(CH₂)_(r)R^(1b),CO₂(CH₂)_(t)R^(1b), O(CH₂)_(t)R^(1b), S(O)_(p)(CH₂)_(r)R^(1d),O(CH₂)_(r)R^(1d), NR³(CH₂)_(r)R^(1d), OC(O)NR³(CH₂)_(r)R^(1d),NR³C(O)NR³(CH₂)_(r)R^(1d), NR³C(O)O(CH₂)_(r)R^(1d), andNR³C(O)(CH₂)_(r)R¹d, provided that R^(1a) forms other than an N-halo,N—S, O—O, or N—CN bond; alternatively, when two R^(1a) groups areattached to the same carbon atom, together with the carbon atom to whichthey are attached they form a 3-6 membered carbocyclic or heterocyclicring consisting of: carbon atoms and 0-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p), this ring being substituted with0-2 R⁴ and 0-3 ring double bonds; R^(1b) is selected from H, CH₃,CH₂CH₃, F, Cl, Br, —CN, —CHO, CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2b),CO₂R^(2b), OC(O)R², CO₂R^(2a), S(O)_(p)R², NR²(CH₂)_(r)OR²,NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(O)NR²R^(2a), SO₂NR²R^(2a),NR²SO₂NR²R^(2a), NR²SO₂R², C(O)NR²SO₂R², SO₂NR²C(O)R², C₃₋₁₀ carbocyclesubstituted with 0-2 R⁴, and 4-10 membered heterocycle consisting ofcarbon atoms and from 1-4 heteroatoms selected from the group consistingof N, O, and S(O)_(p) and substituted with 0-2 R⁴, provided that R^(1b)forms other than an O—O, N-halo, N—S, or N—CN bond; R², at eachoccurrence, is selected from H, CF₃, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂, phenyl substitutedwith 0-2 R^(4b), a benzyl substituted with 0-2 R^(4b), a 5-6 memberedheterocycle-CH₂ group wherein said heterocycle consists of: carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p) and substituted with 0-2 R^(4b), and a 5-6 membered heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b);R^(2a), at each occurrence, is selected from H, CF₃, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂,benzyl, phenyl substituted with 0-2 R^(4b), and 5-6 membered heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b);alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-2 R^(4b) and consistingof: 0-1 additional heteroatoms selected from the group consisting of N,O, and S(O)_(p); R^(2b), at each occurrence, is selected from CF₃, C₁₋₄alkoxy, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substitutedwith 0-2 R^(4b), and 5-6 membered aromatic heterocycle consisting of:carbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p) and substituted with 0-2 R^(4b); R^(2c), at eachoccurrence, is selected from CF₃, OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃,OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substitutedwith 0-2 R^(4b), and 5-6 membered aromatic heterocycle containing from1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p)and substituted with 0-2 R^(4b); R^(2d), at each occurrence, is selectedfrom H, R^(4c), C₁₋₄ alkyl substituted with 0-2 R^(4c), C₃₋₆ carbocyclesubstituted with 0-2 R^(4c), —(CR³R^(3a))—C₃₋₆ carbocycle substitutedwith 0-2 R^(4c), 5-6 membered heterocycle substituted with 0-2 R^(4c)and consisting of: carbon atoms and 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p), and —(CR³R^(3a))-5-6 memberedheterocycle substituted with 0-2 R^(4c) and consisting of: carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p), provided that R^(2d) forms other than a N-halo, N—C-halo,S(O)_(p)-halo, O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O, O—N, O—S, orO—O moiety; R^(2e), at each occurrence, is selected from H, R^(4c), C₁₋₄alkyl substituted with 0-2 R^(4c), C₃₋₆ carbocycle substituted with 0-2R^(4c), —(CR³R^(3a))—C₃₋₆ carbocycle substituted with 0-2 R^(4c), 5-6membered heterocycle substituted with 0-2 R^(4c) and consisting of:carbon atoms and 1-4 heteroatoms selected from the group consisting ofN, O, and S(O)_(p), and —(CR³R^(3a))-5-6 membered heterocyclesubstituted with 0-2 R^(4c) and consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p),provided that R^(2e) forms other than a C(O)-halo or C(O)—S(O)_(p)moiety; R⁴, at each occurrence, is selected from H, ═O, CH₂OR²,(CH₂)₂OR², OR², F, Cl, Br, I, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, —CN, NO₂, NR²R^(2a),CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),NR²C(O)NR²R^(2a), SO₂NR²R^(2a), CF₃, and CF₂CF₃; R^(4a) is selected from—(CR³R^(3g))_(r)-5-6 membered carbocycle substituted with 0-3 R^(4c),—(CR³R^(3g))_(r)-5-6 membered heterocycle substituted with 0-3 R^(4c)and consisting of: carbon atoms and 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p), (CR³R^(3g))_(r)NR^(2d)R^(2d),(CR³R^(3g))_(r)N(→O)R^(2d)R^(2d), (CR³R^(3g))_(r)OR^(2d),(CR³R^(3g))_(r)—NR^(2d)C(O)R^(2e), (CR³R^(3g))_(r)—C(O)R^(2e),(CR³R^(3g))_(r)—OC(O)R^(2e), (CR³R^(3g))_(r)—C(O)NR^(2d)R^(2d),(CR³R^(3g))_(r)—C(O)OR^(2d), (CR³R^(3g))_(r)—NR^(2d)C(O)NR^(2d)R^(2d),(CR³R^(3g))_(r)—NR^(2d)C(O)OR^(2d), (CR³R^(3g))_(r)—SO₂NR^(2d)R^(2d),(CR³R^(3g))_(r)—NR^(2d)SO₂R^(2d), and (CR³R^(3g))_(r)—S(O)_(p)R^(2d),provided that S(O)_(p)R^(2d) forms other than S(O)₂H or S(O)H; R^(4b),at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F, Cl, CH₃,CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a), C(O)R³,CH₂—C(O)R³, C(O)OR^(3c), CH₂—C(O)OR^(3c), NR³C(O)R^(3a),CH₂NR³C(O)R^(3a), C(O)NR³R^(3a), CH₂—C(O)NR³R^(3a), SO₂NR³R^(3a),CH₂SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, CH₂NR³SO₂—C₁₋₄ alkyl, NR³SO₂-phenyl,CH₂NR³SO₂-phenyl, S(O)_(p)CF₃, CH₂S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,CH₂S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, CH₂S(O)_(p)-phenyl, and CF₃;R^(4c), at each occurrence, is selected from ═O, OR², (CR³R^(3a))OR², F,(CR³R^(3a))F, Br, (CR³R^(3a))Br, Cl, (CR³R^(3a))Cl, CF₃, (CR³R^(3a))CF₃,C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₄ alkyl, —CN, (CR³R^(3a))CN, NO₂,(CR³R^(3a))NO₂, NR²R^(2a), (CR³R^(3a))NR²R^(2a), N(→O)R²R^(2a),(CR³R^(3a))N(→O)R²R^(2a), C(O)R^(2c), (CR³R^(3a))C(O)R^(2c),NR²C(O)R^(2b), (CR³R^(3a))NR²C(O)R^(2b), C(O)NR²R^(2a),(CR³R^(3a))C(O)NR²R^(2a), NR²C(O)NR²R^(2a), (CR³R^(3a))NR²C(O)NR²R^(2a),SO₂NR²R^(2a), (CR³R^(3a))SO₂NR²R^(2a), NR²SO₂NR²R^(2a),(CR³R^(3a))NR²SO₂NR²R^(2a), NR²SO₂R^(5a), (CR³R^(3a))NR²SO₂R^(5a),S(O)_(p)R^(5a), (CR³R^(3a))S(O)_(p)R^(5a), CF₃, CF₂CF₃, C₃₋₁₀ carbocyclesubstituted with 0-2 R^(4b), (CR³R^(3a))C₃₋₁₀ carbocycle substitutedwith 0-2 R^(4b), 5-10 membered heterocycle consisting of carbon atomsand from 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p) and substituted with 0-2 R^(4b), and (CR³R^(3a))-5-10 memberedheterocycle consisting of carbon atoms and from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S(O)_(p) and substituted with 0-2R^(4b); R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a),CH₂NR³R^(3a), C(O)R³, CH₂C(O)R³, C(O)OR^(3c), CH₂C(O)OR^(3c),NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl,NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl,S(O)_(p)-phenyl, CF₃, phenyl substituted with 0-2 R⁶, naphthylsubstituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶; and, R⁶, ateach occurrence, is selected from H, OH, OR², F, Cl, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b),CH₂C(O)R^(2b), NR²C(O)R^(2b), SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl.
 4. Acompound according to claim 3, wherein: G is selected from the group:

G₁ is selected from H, C₁₋₄ alkyl substituted with 0-1 R^(1a),CH₂C(O)OR², CH₂C(O)NR²R^(2a), CH₂C(O)NHCH₂CH₂OR², andCH₂C(O)NHCH₂CH₂NR²R^(2a), CH₂C(O)OR², CH₂C(O)NR²R^(2a),CH₂C(O)N(CH₃)CH₂CH₂OR², CH₂C(O)N(CH₃)CH₂CH₂NR²R^(2a),CH₂C(O)NR²CH₂C(O)NR²R^(2a), CH₂C(O)NR²CH₂CH₂C(O)NR²R^(2a),CH₂C(O)NR²CH₂C(O)OR², and CH₂C(O)NR²CH₂CH₂C(O)OR²; A is selected fromone of the following carbocyclic and heterocyclic groups which aresubstituted with 0-2 R⁴; cyclohexyl, phenyl, piperidinyl, piperazinyl,pyridyl, pyrimidyl, thienyl, pyrrolyl, pyrrolidinyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl; B isselected from N(B¹)C(O)C(R³R^(3g))NB²B³,

provided that the central lactam ring and B are attached to differentatoms on A; B¹ is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂;B² is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, and CH(CH₃)₂; B³ isselected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃,CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, C₂₋₅ alkyl substituted with 1R^(4c), —(CH₂)₀₋₁-3-6 membered carbocycle substituted with 0-1 R⁵, and a—(CH₂)₀₋₁-5-6 membered heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-1 R⁵; ring Q is a 6-7 membered lactam consisting of,in addition to the amide group shown, carbon atoms and 0-1 heteroatomsselected from NR^(4c), O, S, S(O), and S(O)₂, wherein: 0-2 double bondsare present within the ring and the ring is substituted with 0-2 R^(4a);alternatively, ring Q is a 5-7 membered lactam to which another ring isfused, wherein: the lactam consists of, in addition to the shown amidegroup, carbon atoms and 0-1 heteroatoms selected from NR^(4c), O, S,S(O), and S(O)₂ and 0-1 double bonds are present within the ring; thefusion ring is phenyl; ring Q, which includes the lactam ring and thefusion ring, is substituted with 0-2R^(4a); ring Q¹ is selected fromC(CH₃)₂, C(CH₂CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentanonyl, cyclohexyl, cyclohexanonyl, pyrrolidinyl,pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydrofuranyl, andtetrahydropyranyl, and, when Y is a ring, Y is substituted with 0-1 R⁴;R^(1a) is selected from H, R^(1b), C(CH₃)₂R^(1b), CH(CH₃)R^(1b),CH₂R^(1b), CH₂CH₂R^(1b), CH₂OCH₂CH₂R^(1b), OCH₂CH₂R^(1b),(CH₂)_(r)NR³CH₂CH₂R^(1b), NR³(CR³R^(3a))_(t)R^(1c),O(CR³R^(3a))_(t)R^(1c), (CH₂)_(r)C(O)NR²(CH₂)_(r)R^(1b),S(O)_(p)(CH₂)_(r)R^(1d), O(CH₂)_(r)R^(1d), NR³(CH₂)_(r)R^(1d),OC(O)NR³(CH₂)_(r)R^(1d), NR³C(O)NR³(CH₂)_(r)R^(1d),NR³C(O)O(CH₂)_(r)R^(1d), and NR³C(O)(CH₂)_(r)R^(1d), provided thatR^(1a) forms other than an N-halo, N—S, O—O, or N—CN bond;alternatively, when two R^(1a) groups are attached to the same carbonatom, together with the carbon atom to which they are attached they forma 3-10 membered carbocyclic or heterocyclic ring consisting of: carbonatoms and 0-4 heteroatoms selected from the group consisting of N, O,and S(O)_(p), this ring being substituted with 0-2 R⁴ and 0-2 ringdouble bonds; R^(1b) is selected from H, CH₃, CH₂CH₃, F, Cl, Br, —CN,—CHO, CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2b), CO₂R^(2b), OC(O)R²,CO₂R^(2a), S(O)_(p)R², NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)NR²R^(2a),C(O)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂R², C(O)NR²SO₂R²,SO₂NR²C(O)R², C₃₋₆ carbocycle substituted with 0-2 R⁴, and 4-10 memberedheterocycle consisting of carbon atoms and from 1-4 heteroatoms selectedfrom the group consisting of N, O, and S(O)_(p) and substituted with 0-2R⁴, provided that R^(1b) forms other than an O—O, N-halo, N—S, or N—CNbond; R^(2a), at each occurrence, is selected from H, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂,and benzyl; alternatively, R² and R^(2a), together with the atom towhich they are attached, combine to form a 5 or 6 membered saturated,partially saturated or unsaturated ring substituted with 0-1 R^(4b) andconsisting of: 0-1 additional heteroatoms selected from the groupconsisting of N, O, and S(O)_(p); R^(2b), at each occurrence, isselected from OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃,CH₂CH₂CH₃, CH(CH₃)₂, benzyl, phenyl substituted with 0-1 R^(4b), and 5-6membered aromatic heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-1 R^(4b); R^(2c), at each occurrence, is selectedfrom OH, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, benzyl, phenyl substituted with 0-1 R^(4b), and 5-6 memberedaromatic heterocycle containing from 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p) and substituted with 0-1 R^(4b);R^(2d), at each occurrence, is selected from H, R^(4c), C₁₋₄ alkylsubstituted with 0-2 R^(4c), C₃₋₆ carbocycle substituted with 0-2R^(4c), —(CH₂)—C₃₋₆ carbocycle substituted with 0-2 R^(4c), 5-6 memberedheterocycle substituted with 0-2 R^(4c) and consisting of: carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p), and —(CH₂)-5-6 membered heterocycle substituted with 0-2R^(4c) and consisting of: carbon atoms and 1-4 heteroatoms selected fromthe group consisting of N, O, and S(O)_(p), provided that R^(2d) formsother than a N-halo, N—C-halo, S(O)_(p)-halo, O-halo, N—S, S—N,S(O)_(p)—S(O)_(p), S—O, O—N, O—S, or O—O moiety; R^(2e), at eachoccurrence, is selected from H, R^(4c), C₁₋₄ alkyl substituted with 0-2R^(4c), C₃₋₆ carbocycle substituted with 0-2 R^(4c), —(CH₂)—C₃₋₆carbocycle substituted with 0-2 R^(4c), 5-6 membered heterocyclesubstituted with 0-2 R^(4c) and consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p),and —(CH₂)-5-6 membered heterocycle and consisting of: carbon atoms and1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p), provided that R^(2e) forms other than a C(O)-halo orC(O)—S(O)_(p) moiety; R⁴, at each occurrence, is selected from H, ═O,OH, OR², CH₂OR², (CH₂)₂OR², F, Br, Cl, I, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, C(CH₃)₃, NR²R^(2a),CH₂NR²R^(2a), (CH₂)₂NR²R^(2a), C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a),SO₂NR²R^(2a), CF₃, and CF₂CF₃; R^(4a) is selected from—(CR³R^(3g))_(r)-5-6 membered carbocycle substituted with 0-3 R^(4c),—(CR³R^(3g))_(r)-5-6 membered heterocycle substituted with 0-3 R^(4c)and consisting of: carbon atoms and 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p), (CR³R^(3g))_(r)NR^(2d)R^(2d),(CR³R^(3g))_(r)N(→O)R^(2d)R^(2d), (CR³R^(3g))_(r)OR^(2d),(CR³R^(3g))_(r)—C(O)NR^(2d)R^(2d), (CR³R^(3g))_(r)—NR^(2d)C(O)R^(2e),(CR³R^(3g))_(r)—C(O)R^(2e), (CR³R^(3g))_(r)—NR^(2d)C(O)NR^(2d)R^(2d),(CR³R^(3g))_(r)—NR^(2d)C(O)OR^(2d), (CR³R^(3g))_(r)—NR^(2d)SO₂R^(2d),and (CR³R^(3g))_(r)—S(O)_(p)R^(2d), provided that S(O)_(p)R^(2d) formsother than S(O)₂H or S(O)H; R^(4b), at each occurrence, is selected fromH, ═O, OR³, CH₂OR³, F, Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂,NR³R^(3a), CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c), NR³C(O)R^(3a),C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂-phenyl,S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, and CF₃; R^(4c), at eachoccurrence, is selected from ═O, OR², CH₂OR², F, Br, Cl, CF₃, CH₃,CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, CH₂CH₂CH₂CH₃, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,C(CH₃)₃, C₂₋₃ alkenyl, C₂₋₃ alkynyl, —CN, NO₂, NR²R^(2a), CH₂NR²R^(2a),N(→O)R²R^(2a), CH₂N(→O)R²R^(2a), C(O)R^(2c), CH₂C(O)R^(2c),NR²C(O)R^(2b), CH₂NR²C(O)R^(2b), C(O)NR²R^(2a), CH₂C(O)NR²R^(2a),SO₂NR²R^(2a), CH₂SO₂NR²R^(2a), NR²SO₂R^(5a), CH₂NR²SO₂R^(5a),S(O)_(p)R^(5a), CH₂S(O)_(p)R^(5a), CF₃, CF₂CF₃, C₃₋₆ carbocyclesubstituted with 0-2 R^(4b), (CH₂)C₃₋₆ carbocycle substituted with 0-2R^(4b), 5-6 membered heterocycle consisting of carbon atoms and from 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p) andsubstituted with 0-2 R^(4b), and (CH₂)-5-6 membered heterocycleconsisting of carbon atoms and from 1-4 heteroatoms selected from thegroup consisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b);R⁵, at each occurrence, is selected from H, ═O, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, OR³, CH₂OR³, F, Cl, —CN, NO₂, NR³R^(3a), CH₂NR³R^(3a), C(O)R³,C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂—C₁₋₄alkyl, NR³SO₂-phenyl, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, CF₃, phenylsubstituted with 0-2 R⁶, naphthyl substituted with 0-2 R⁶, and benzylsubstituted with 0-2 R⁶; and, R⁶, at each occurrence, is selected fromH, OH, OR², F, Cl, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, —CN, NO₂,NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), CH₂C(O)R^(2b), NR²C(O)R^(2b), andSO₂NR²R^(2a).
 5. A compound according to claim 4, wherein: G is selectedfrom:

A is selected from one of the following carbocyclic and heterocyclicgroups which are substituted with 0-2 R⁴; cyclohexyl, phenyl, pyridyl,and pyrimidyl; B is selected from the group:

alternatively, B is selected from N(B¹)C(O)C(R³R^(3g))NB²B³ and

B¹ is selected from H, CH₃, CH₂CH₃, and CH₂CH₂CH₃; B² is selected fromH, CH₃, and CH₂CH₃; B³ is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH₂CH₂CH₃, C(CH₃)₃, CH(CH₃)CH₂CH(CH₃)₂, CH₂CH₂OH,CH(CH₃)CH₂OH, CH(phenyl)CH₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl,and CH₂-cyclopropyl; ring Q¹ is selected from C(CH₃)₂, C(CH₂CH₃)₂,cyclopropyl, cyclobutyl, cyclopentyl, 2-cyclopentanonyl, cyclohexyl,2-cyclohexanonyl, pyrrolidinyl (attached to A and R^(4a) at the2-position), pyrrolidinyl (attached to A and R^(4a) at the 3-position),2-pyrrolidinonyl (attached to A and R^(4a) at the 3-position),piperidinyl (attached to A and R^(4a) at the 4-position), 4-piperdinonyl(attached to A and R^(4a) at the 3-position), tetrahydrofuranyl, andtetrahydropyranyl (attached to A and R^(4a) at the 4-position); R^(1a)is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH₂(CH₃)₂, CF₃, CH₂CF₃,OCH₃, CH₂OH, C(CH₃)₂OH, CH₂OCH₃, NH₂, CH₂NH₂, NHCH₃, CH₂NHCH₃, N(CH₃)₂,CH₂N(CH₃)₂, CO₂H, COCH₃, CO₂CH₃, CH₂CO₂CH₃, NHCOCH₃, S(O)CH₃,CH₂S(O)CH₃, S(O)₂CH₃, CH₂S(O)₂CH₃, C(O)NH₂, CH₂C(O)NH₂, SO₂NH₂,CH₂SO₂NH₂, NHSO₂CH₃, CH₂NHSO₂CH₃, NHSO₂NHCH₃, NHSO₂N(CH₃)₂, NHCO₂R^(2a),NHC(O)NHR^(2a), CH₂OCH₂CH₂NR²R^(2a), C(O)NR²R^(2a), CH₂CH₂OR²,CH₂C(O)NR²CH₂CH₂OR², C(O)NHCH₂CH₂NR²R^(2a), CH₂C(O)NHCH₂CH₂NR²R^(2a),C(O)NCH₃CH₂CH₂NR²R^(2a), CH₂C(O)NCH₃CH₂CH₂NR²R^(2a),CH₂NHCH₂CH₂NR²R^(2a), CH₂N(CH₃)CH₂CH₂NR²R^(2a), phenyl substituted with0-2 R^(4b), —CH₂-phenyl substituted with 0-2 R^(4b), 5-10 memberedaromatic heterocycle consisting of carbon atoms and from 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-2 R^(4b), and —CH₂-5-10 membered aromatic heterocycle consistingof carbon atoms and from 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p) and substituted with 0-2 R^(4b),provided that R^(1a) forms other than an N-halo, N—S, O—O, or N—CN bond;R², at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, CH₂CH₂CH₂NMe₂, phenylsubstituted with 0-1 R^(4b), benzyl substituted with 0-1 R^(4b), 5membered aromatic heterocycle-CH₂ group wherein the heterocycle consistsof: carbon atoms and 1-4 heteroatoms selected from the group consistingof N, O, and S(O)_(p) and substituted with 0-1 R^(4b) and 5 memberedaromatic heterocycle consisting of: carbon atoms and 1-4 heteroatomsselected from the group consisting of N, O, and S(O)_(p) and substitutedwith 0-1 R^(4b); R^(2a), at each occurrence, is selected from H, CH₃,and CH₂CH₃, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH₂NMe₂, and CH₂CH₂CH₂NMe₂,alternatively, R² and R^(2a), together with the atom to which they areattached, combine to form a 5 or 6 membered saturated, partiallysaturated or unsaturated ring substituted with 0-1 R^(4b) and consistingof: 0-1 additional heteroatoms selected from the group consisting of N,O, and S(O)_(p); R^(2b), at each occurrence, is selected from OCH₃,OCH₂CH₃, CH₃, and CH₂CH₃; R^(2c), at each occurrence, is selected fromOH, OCH₃, OCH₂CH₃, CH₃, and CH₂CH₃; R^(2d), at each occurrence, isselected from H, C₁₋₄ alkyl substituted with 0-1 R^(4c), C₃₋₆ cycloalkylsubstituted with 0-2 R^(4c), phenyl substituted with 0-2 R^(4c), and a5-6 membered aromatic heterocycle consisting of: carbon atoms and 1-4heteroatoms selected from the group consisting of N, O, and S(O)_(p),provided that R^(2d) forms other than a N-halo, N—C-halo, S(O)_(p)-halo,O-halo, N—S, S—N, S(O)_(p)—S(O)_(p), S—O, O—N, O—S, or O—O moiety;R^(2e), at each occurrence, is selected from H, C₁₋₄ alkyl substitutedwith 0-1 R^(4c), C₃₋₆ cycloalkyl substituted with 0-2 R^(4c), phenyl,substituted with 0-2 R^(4c), and 5-6 membered aromatic heterocycleconsisting of: carbon atoms and 1-4 heteroatoms selected from the groupconsisting of N, O, and S(O)_(p), provided that R^(2e) forms other thana C(O)-halo or C(O)—S(O)_(p) moiety; R^(4a) is selected fromNR^(2d)R^(2d), CH₂NR^(2d)R^(2d), N(→O)R^(2d)R^(2d),CH₂N(→O)R^(2d)R^(2d), CH₂OR^(2d), C(O)R^(2e), C(O)NR^(2d)R^(2d),CH₂C(O)NR^(2d)R^(2d), NR^(2d)C(O)R^(2e), CH₂NR^(2d)C(O)R^(2e),NR^(2d)C(O)NR^(2d)R^(2d), CH₂NR^(2d)C(O)NR^(2d)R^(2d),NR^(2d)C(O)OR^(2d), CH₂NR^(2d)C(O)R^(2d), NR^(2d)SO₂R^(2d),CH₂NR^(2d)SO₂R^(2d), S(O)_(p)R^(2d), CH₂S(O)_(p)R^(2d), 5-6 memberedcarbocycle substituted with 0-2 R^(4c), —(CH₂)-5-6 membered carbocyclesubstituted with 0-2 R^(4c), 5-6 membered heterocycle substituted with0-2 R^(4c) and consisting of: carbon atoms and 1-4 heteroatoms selectedfrom the group consisting of N, O, and S(O)_(p), and —(CH₂)-5-6 memberedheterocycle substituted with 0-2 R^(4c) and consisting of: carbon atomsand 1-4 heteroatoms selected from the group consisting of N, O, andS(O)_(p) provided that S(O)_(p)R^(2d) forms other than S(O)₂H or S(O)H;and, R^(4b), at each occurrence, is selected from H, ═O, OR³, CH₂OR³, F,Cl, CH₃, CH₂CH₃, NR³R^(3a), CH₂NR³R^(3a), C(O)R³, C(O)OR^(3c),NR³C(O)R^(3a), C(O)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂-phenyl, S(O)₂CH₃,S(O)₂-phenyl, and CF₃; and, R^(4c) is selected from ═O, OH, OCH₃,OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂,CH═CH₂, CH≡CH, CH₂OH, CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃, CH₂OCH(CH₃)₂,F, Br, Cl, CF₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2c), CH₂C(O)R^(2c),NR²C(O)R^(2b), CH₂NR²C(O)R^(2b), C(O)NR²R^(2a), CH₂C(O)NR²R^(2a),SO₂NR²R^(2a), CH₂SO₂NR²R^(2a), NR²SO₂R^(5a), CH₂NR²SO₂R^(5a),S(O)_(p)R^(5a), and CH₂S(O)_(p)R^(5a).
 6. A compound according to claim5, wherein the compound is selected from:

B is selected from:

R^(2d), at each occurrence, is selected from H, CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CH₂CH(CH₃)₂, CH₂CCH, CH₂CH₂OH, CH₂C(O)NH₂,cyclopropyl, CH₂-cyclopropyl, cyclobutyl, cyclopentyl, and thiazolyl;R^(2e), at each occurrence, is selected from CH₃, CH₂CH₃, CH₂CH₂CH₃,CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CH₂CH(CH₃)₂, CH₂-cyclopropyl, cyclopropyl, andcyclopentyl; R^(4a) is substituted with 0-2 R^(4c) and selected frommorpholine, 1,1-dioxo-thiomorpholine, dihydropyridine, piperidine,piperazine, pyrrolidine, imidazole, imidazoline, imidazolidine,oxazoline, and thiazoline; and, R^(4c) is selected from ═O, OH, OCH₃,and CH₃.
 7. A compound according to claim 6, wherein the compound isselected from:


8. A compound according to claim 1, wherein the compound is selectedfrom the group:N-{4-[3-(6-chloro-naphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]-phenyl}-N-methyl-2-pyrrolidin-1-yl-acetamide;6-chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-pyrrolidin-3-yl}-amide;6-chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-pyrrolidin-3-yl}-amide;6-chloro-naphthalene-2-sulfonic acid{2-oxo-1-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-piperidin-3-yl}-amide;and 6-chloro-thieno[2,3-b]pyridine-2-sulfonic acid{2-oxo-1-[4-(1-pyrrolidin-1-ylmethyl-cyclopropyl)-phenyl]-piperidin-3-yl}-amide;or a pharmaceutically acceptable salt form thereof.
 9. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.
 10. A method for treating athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt form thereof.
 11. A method according toclaim 10, wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, and thromboembolic disorders inthe chambers of the heart.
 12. A method according to claim 10, whereinthe thromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, first myocardial infarction, recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom (a) prosthetic valves or other implants, (b) indwelling catheters,(c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) otherprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis.
 13. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 2 or a pharmaceutically acceptable saltthereof.
 14. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 3 or a pharmaceutically acceptable saltthereof.
 15. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 4 or a pharmaceutically acceptable saltthereof.
 16. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 5 or a pharmaceutically acceptable saltthereof.
 17. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 6 or a pharmaceutically acceptable saltthereof.
 18. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 7 or a pharmaceutically acceptable saltthereof.
 19. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of claim 8 or a pharmaceutically acceptable saltthereof.